Category: Neurology

Back to IMS-III: It’s the Collaterals

The year 2012 was dark times for endovascular treatment for acute ischemic stroke.  MR-RESCUE, IMS-3, and SYNTHESIS were all decidedly negative, and their failures trotted out in the New England Journal of Medicine.

This current year has been much better – a trove of trials following the initial positive result of MR-CLEAN, the key features of which were:

  • Improved time from onset to endovascular intervention.
  • Effective recanalization, far exceeding that of tPA.
  • Narrowly selected patients guided by imaging criteria.

Of those three key features, it appears the universally critical items are primarily the last two – recanalization and salvageable tissue.

This is a reanalysis of IMS-3, looking retrospectively at 78 patients from the trial for whom cerebral angiograms were available.  They looked specifically a the “capillary index score”, essentially, an imaging-based classification of the collateral circulation near a lesion.  In an outcomes-blinded fashion, the authors calculated the CIS for each, and then correlated the results with functional outcomes.  The numbers are small, but the numbers achieving good outcomes are consistent and logical:

  • Poor CIS, unsuccessful recanalization: 1/15 (7%)
  • Poor CIS, successful recanalization: 2/15 (13%)
  • Good CIS, unsuccessful recanalization: 5/24 (25%)
  • Good CIS, successful recanalization: 17/24 (71%)

Essentially another brick in the small wall of evidence favoring the necessity of an imaging-based strategy to narrowly select patients for endovascular intervention, rather than a non-selected time-based strategy.

“Relative Influence of Capillary Index Score, Revascularization, and Time on Stroke Outcomes From the Interventional Management of Stroke III Trial”
http://www.ncbi.nlm.nih.gov/pubmed/25953374

Muddying Acute Stroke With Recanalization vs. Reperfusion

The conceptual mainstay of interventions for acute ischemic stroke is recanalization.  The “clot buster” – tPA.  The “clot retriever” – the endovascular stent devices.  These are interventions aimed at opening an occluded vessel and restoring flow.

But, as it turns out, recanalization is only part of the story.  The other half – and the not fully-appreciated utlimate goal – is reperfusion.

This is a small analysis of 46 patients from a prospective, multicenter database undergoing acute magnetic resonance angiography following acute ischemic stroke.  All patients had visible sites of arterial occlusion accompanied by a measurable ischemic penumbra.  Furthermore, each of these patients underwent subsequent MRA within 6 hours to evaluate recanalization and reperfusion.

Most of the occlusions were proximal, large intracranial vessels – ICA, M1, M2, and M3.  Most patients – 34 – received intravenous tPA, while the remaining 12 were managed conservatively.  Recanalization occurred in 29% of patients receiving tPA and 25% of those not.  However, reperfusion occurred regardless of recanalization – 46% of those receiving tPA and 33% of those not.  Univariate analyses regarding improvement in NIHSS and functional outcomes showed the strongest predictor (and, given the small sample, really the only predictor) was not recanalization – it was reperfusion.

Now, recanalization is certainly the most effective method for achieving reperfusion – hence the increasingly favorable results seen in the endovascular trials as device reliability improved.  That said, clearly, some of our thinking regarding patient selection is flawed by a narrow approach focused solely on recanalization.  There are many logistical hurdles and additional studies needed to translate some of this knowledge into practice, but it appears it may be quite reasonable to withhold acute recanalization therapy if reperfusion has already been spontnaeously, naturally achieved.

The goal, after all – despite the best efforts of pharmaceutical backers – should not be to expand the shotgun spread of recanalization therapies to the largest possible cohort.  Rather, we ought to be focusing on finding additional stratification strategies, with a goal of improving patient selection to those with the greatest magnitude of potential benefit.

“Reperfusion Within 6 Hours Outperforms Recanalization in Predicting Penumbra Salvage, Lesion Growth, Final Infarct, and Clinical Outcome”
http://www.ncbi.nlm.nih.gov/pubmed/25908463

Using CTA to Predict tPA Failures

tPA, the “proven” therapy foisted inappropriately on Emergency Medicine and our patients, doesn’t work.

Rather – as I’ve said before – it simply doesn’t work the way we’ve been taught.

The core concepts of the theoretical utility of tPA for ischemic stroke are demonstrated nicely in the new endovascular trials.  Patients do well, better than the natural course of their disease if:

  • There is significant viable brain distal to the vascular occlusion as a result of collateral circulation.
  • The vessel is rapidly and reliably opened.

Both these criteria were met in the new endovascular trials, requiring imaging evidence of a small infarct core and use of modern retrieval devices.  However, the broad population being pushed as candidates for tPA are not as fortunate – the key feature being the abysmal recanalization rate of tPA, only 46% in a meta-analysis of tiny case series from mostly the ‘90s.  Comparatively, in the same report, early spontaneous recanalization was present in 24%.  So, obviously, there’s only even a 1 in 5 chance a patient will receive an additive benefit from tPA for recanalization – which, with some heterogeneity, means our NNT has a maximum upper bound if we treat an unselected population of all-comers.

This study is a small case series from the ongoing PRove-IT study, looking specifically at, essentially, the permeability of intracranial thrombi.  These authors hypothesized this might be an important predictor of recanalization because, after all, if there’s no flow through an impermeable occlusion, tPA can never fully contact the substrate of interest.  These authors used CT angiography to estimate occult anterograde flow versus retrograde flow, and followed-up recanalization following tPA.

There are only 66 patients in this small observational study, but the results are rather compelling.  They estimated 17 (25.8%) of patients had some minimal anterograde flow through the occluded vessel.  These patients, with some detectable flow, had a 66.7% recanalization rate.  Conversely, the 49 patients without any residual anterograde flow had a recanalization rate of only 29.7% – a rate not dissimilar to spontaneous.  And, outcomes followed recanalization – logically, considering detectable anterograde flow and effective destruction of the occlusion are highly favorable features.

The moral of the story?  It’s quite clear there are promising venues for determining which patients have the best chance to benefit from tPA – and those for whom the harms exceed those chances.  The perpetual “tPA for all!” call being added to guidelines and quality measures is a product of conflict-of-interest and corporate sponsorship, not good medicine – and we can do better, if we simply cared to investigate.

“Occult Anterograde Flow Is an Under-Recognized But Crucial Predictor of Early Recanalization With Intravenous Tissue-Type Plasminogen Activator”
http://www.ncbi.nlm.nih.gov/pubmed/25700286

The Case of the Bloody Lumbar Punctures

Modern evaluation for aneurysmal subarachnoid hermorrhage, with some debate, may include definitive non-contrast CT performed within six hours of symptom onset.  The traditional evaluation, and still recommended beyond six hours, involves a lumbar puncture, looking for red blood cells or xanthrochromia.

This latest tale of woe from Jeff Perry’s SAH data details the pragmatic effectiveness of the traditional pathway, focusing on the primary confounder: traumatic taps.  They report on 1,739 patients undergoing lumbar puncture as part of this evaluation, and, unfortunately, the numbers are grim:  641 (36.8%) samples were abnormal in the final tube of CSF collected.  However, it isn’t so bad – 476 of those had fewer than 100 RBCs x 10^6/L, with many having only a handful of cells.  But, still, that leaves 165 patients with fairly substantial numbers of RBCs in their CSF.

Because, all told, only 15 received a final diagnosis of aneurysmal SAH.

Why is this so grim?  Because 419 of these 626 patients with RBCs on their LP subsequently were subjected to angiography – with 404 of them negative.

And xanthrochromia?  Some predictive value – 7 of 15 patients diagnosed with SAH displayed xanthrochromia, but, obviously there were 8 patients with SAH who did not, along with 16 instances of xanthrochromia in patients without SAH.

The final gist of the paper is to generate a 100% sensitive cut-off to exclude SAH – for which the authors choose 2000 x 10^6 and absent xanthrochromia.  This results in a specificity of 91.2% and a positive LR or 11.4.  This is a pretty good positive LR, but, unfortunately, given such a vanishingly rare disease, the PPV was only 21.4% in their cohort.

However, one major flaw in this study is it doesn’t usefully describe the population of true interest to Emergency Physicians – the test characteristics of those with a negative CT and a positive LP.  There were 77 patients who did not undergo CT prior to LP, but, more importantly, 10 of the patients included in this cohort had visible SAH on CT recognized by the staff radiologist, but not the Emergency Physician.  Therefore, if you practice in a setting without neuroradiology coverage, this is generalizable.  Otherwise, we can exclude those 10 cases and boggle at the massive resource utilization in terms of LPs and angiography in order to pick up just 5 cases of occult aneurysmal SAH.

In patient-oriented terms – based on these data – the risk of SAH after a negative CT performed greater than 6 hours after onset is about 1 in 330.  Using their cut-off of 2000 x10^6, the chance of a true positive LP is about 1 in 12.  A vast improvement, to be sure, but probably still not a pathway very many patients are going to choose when presented with these odds.

“Differentiation between traumatic tap and aneurysmal subarachnoid hemorrhage: prospective cohort study”
http://www.ncbi.nlm.nih.gov/pubmed/25694274 (free fulltext)

Inappropriately Promoted tPA “Drip and Ship” Safety

“More community hospitals are giving a powerful clot-busting medication to stroke victims, improving their chances of survival and recovery, new research shows.”

This statement comes from the American Heart Association press release regarding this synopsis of the Get-With-the-Guideline Registry.  Part of this statement is true – more community hospitals are using tPA for acute ischemic stroke.  In this review of 44,667 patients treated with tPA over the past decade, 23.5% received tPA outside of a specialized stroke or academic center.

The second half of this press statement is false.

Patients treated by the “drip and ship” method, as community administration of tPA is described, did not have an improved chance of survival.  Patients treated at community hospitals were younger, had less-severe strokes, and had fewer prior strokes – yet their in-hospital mortality was 10.9%, compared with 9.7%.  Additionally, their rate of symptomatic intracranial hemorrhage was 5.7% compared with 5.2%, and they had 1.8% serious tPA-related complications, compared with 1.6%.  These small absolute differences are magnified when adjustments are made for baseline comorbidities, and, in fact the OR for in-hospital mortality increases to 1.23 or 1.33, depending on the precise statistics pursued.  So, of course, the logical leading sentence of the Discussion is:

“In this study of >40000 patients with acute ischemic stroke treated with IV thrombolysis throughout the United States, drip and ship thrombolysis was …. safe.”

A better leading sentence to their Discussion might rather suggest the “drip and ship” model is, in fact, less safe than typical thrombolysis.  Further, they might better suggest the “drip and ship” model should be curtailed while further investigation into additive risks are performed, or to confirm the effects noted from this somewhat dodgy registry data.  But, these authors focus more on explaining away this inconsistency with their narrative than calling for safer, narrower administration of tPA.  After all, these authors are well-funded by industry – including one affiliated with MGH TeleHealth, providing telestroke-enabled thrombolysis:

Dr Sheth is a member of the Get with the Guidelines (GWTG)- Stroke Clinical Workgroup, and he is a Co-Principal Investigator and Executive Committee member for Glyburide Advantage in Malignant Edema and Stroke-Remedy Pharmaceuticals (GAMES-RP), a phase II–trial to prevent swelling in patients with large stroke, funded by Remedy Pharmaceuticals, Inc. Dr Smith is a member of the GWTG- Stroke Workgroup. Dr Kleindorfer discloses speaking engagements. Dr Fonarow is a member of the GWTG Steering Committee; receipt of research support (to the institution) from Patient-Centered Outcomes Research Institute, and he is an employee of the University of California that holds a patent on retriever devices for stroke. Dr Schwamm is the chair of the GWTG-Stroke Clinical Workgroup, a principal investi- gator of the National Institutes of Health–funded MR WITNESS (A Study of Intravenous Thrombolysis With Alteplase in MRI-Selected Patients) trial of extended window thrombolysis for which Genentech provides supplemental site payments and alteplase free of charge, a member of the international steering committee of the Desmoteplase in Acute Ischemic Stroke (DIAS) 3 and 4 trials of extended window thrombolysis, and the director of Massachusetts General Hospital (MGH) TeleHealth. The MGH provides a broad array of telehealth services to hospitals in New England, including telestroke-enabled thrombolysis. Dr Grau-Sepulveda reports no conflicts.

Perhaps the new ACEP Clinical Policy statement can explicitly address such settings in their “systems in place” language.

“Drip and Ship Thrombolytic Therapy for Acute Ischemic Stroke”

Christmas Comes Early for Endovascular Therapy in Stroke

Quite literally, in fact, considering the timing of the publication of MR-CLEAN – and, now, the triple fall-out from those results.

Due to the positive findings presented by the MR-CLEAN investigators in December 2014, three other ongoing major endovascular trials used this opportunity to check their results early.  ESCAPE, EXTEND-IA, and SWIFT-PRIME – all products of the Covidien Solitaire FR clinical trial machine – ceased recruitment and looked to see if they’d met statistical measures of efficacy.  Obviously, if you’re reading about all three of these trials here today – presented at the International Stroke Conference yesterday – they all found the results they hoped.  ESCAPE and EXTEND-IA were published simultaneously in the NEJM, while SWIFT-PRIME is still in the manuscript drafting stages.

The more robust of the two trials is ESCAPE, whose original target enrollment was 500 patients based on a primary outcome of “ordinal shift analysis” on the modified Rankin scale.  The important feature of all these new endovascular trials is the eligibility population: proximal, large-vessel occlusions with imaging-based evidence of moderate-to-good collateral supply surrounding a small infarct core.  In this particular trial, it was proximal internal carotid or middle cerebral artery trunk, an ASPECTS of 6 to 10, and 50% or more filling of the local pial arterial circulation.  Interestingly, this trial enrolled patients with symptoms out to 12 hours from onset – and did not require pretreatment with intravenous alteplase before intervention.

Ignoring their “ordinal shift analysis” nonsense that only serves to distort the effect size, the key results that matter are these:  in the 316 patients enrolled, mRS 0-2 was 53.0% in the endovascular cohort and 29.3% in the control cohort.  Deaths were improved to 10.4% from 19.0%, despite a small increase in sICH of 3.6% to 2.7%.  3 patients suffered access site hematomas and one retriever perforated the middle cerebral artery.  Pretty good, frankly, for a cohort with a median NIHSS of 16.  Interestingly, 45 patients underwent endovascular intervention without receiving alteplase, and 58% achieved mRS 0-2 – although 20% died.

EXTEND-IA was a much smaller trial, targeting only 100 patients, with coprimary outcomes of reperfusion and NIHSS improvement at 24 hours.  Again, these investigators targeted proximal occlusions with radiographic evidence of salvageable “ischemic penumbra”.  They stopped at 70 patients, again, because they’d met their own complex statistical criteria for efficacy.  All patients in this trial received alteplase within 4.5 hours prior to endovascular intervention.  Finally, yet again, ignoring their specific primary outcomes, the result of interest:  mRS 0-2 was achieved by 71% in the endovascular group compared with 40% in the alteplase-only group.  Deaths were improved to 9% from 20%, although this did not reach statistical significance owing to the small sample size.  Reperfusion and infarct region growth at 24 hours also favored the endovascular cohort, as did the measures of early neurologic improvement.

There are many tiny oddities worth picking over in these trials – and, no doubt, their data will be picked over for further clues and hypotheses.  SWIFT-PRIME was similarly positive, but those data were not yet available for full review.  And, finally, we will all have to come to terms with the early termination of all these trials based on MR-CLEAN.  The sponsor, obviously, is ready to make endovascular treatment the (profitable) standard of care.  However, the full enrollment from these trials would have provided additional information regarding potentially dangerous subgroups.  One hopes there will be ongoing endovascular registries going forward to identify any such patterns.

The key take-home, however, is endovascular therapy for acute stroke has probably finally arrived.  After a decade-and-a-half of generally failed trials, it seems the devices and patient selection have finally improved to the point of clinical utility.  For patients with collateral flow and one of these accessible lesions, it seems clear this therapy should be provided – and neither time of onset or tPA use matter as much as viable brain tissue.  But the obvious key, as shown in MR-CLEAN, is patient selection – ESCAPE only managed to enroll 1.4 patients per month per center, while EXTEND-IA screened 7,798 stroke patients over two years to come up with 70.  This therapy is very much so not for everyone – though, no doubt, Covidien hopes it will become so beyond the eligibility population identified here.

But, for the first time ever, if I were to have one of these specific types of heavily disabling strokes, this is probably the first advanced stroke intervention I’d willingly choose.

“Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection”
http://www.nejm.org/doi/full/10.1056/NEJMoa1414792

“Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1414905

The Incredible Power of Drug Cost on Treatment Response

Everyone is familiar with the placebo and nocebo effects – when the expectation of benefit or harm produces positive or negative effects, respectively.  Impressively, however, the power of such effects can be modulated on another level by incorporating cost into the placebo effect.

This fascinating little study tested the effect of two different placebo medications on motor and brain activation in patients suffering from Parkinson’s disease.  Initially, each patient received motor and fMRI testing before and after levodopa administration.  Then, on a subsequent visit, patients received subcutaneous injections of saline 4 hours apart – with participants being told each was the same novel dopamine antagonist, one of which was manufactured using a “cheap” manufacturing process and one using an “expensive” process.  Each participant again received motor and fMRI testing following each injection.

As somewhat expected, each placebo injection produced some improvement in motor function – with the effect reaching statistical significance and almost 30% improvement from baseline for the “expensive” placebo.  Even more impressive, the “expensive” placebo was not too far off the effects of levodopa, which produced approximately a 50% improvement in motor symptoms from baseline.  Most entertainingly, however, the placebo effects were even present on fMRI imaging.  The “expensive” placebo showed brain activation levels similar to levodopa, while the “cheap” placebo had a differing distribution of activity apparently consistent with increased effort.

Yet again, the very real power of placebo – with its magnitude of effect tied to expectations related to cost!

“Placebo effect of medication cost in Parkinson disease”
http://www.ncbi.nlm.nih.gov/pubmed/25632091

Inside a Neurologist’s Mind: tPA For Everyone!

We all have our anecdotal stories from academic medical centers staffed by stroke neurologists, cases in which they have called for thrombolytic therapy in acute ischemic stroke for profoundly inappropriate candidates.  Hearing such sad tales, one hopes such rogue uses of lytics are the lunatic fringe, isolated cases of madness and zealotry.

But, no.

This survey of general and vascular neurologists at two academic institutions in New York demonstrates such aggressive use of tPA for stroke is the pervasive norm, rather than an isolated occurrence.  These authors provided 40 clinicians with a survey consisting of 110 case scenarios of patients presenting with symptoms of acute stroke.  These case scenarios were further stratified by NIHSS, with 22 cases each of NIHSS 1 through 5.  Of the 17 clinicians responding, it was almost unanimous they would use tPA for all cases of NIHSS 3, 4, and 5.  Neurologists would use lytics 57% of the time at NIHSS 2, and 37% of the time with NIHSS 1.

Now, the NIHSS is non-linear, and significant disability can be present at NIHSS 1 and 2 – but even remotely considering lysis at NIHSS 1 or 2 should be the exception rather than an almost balanced split.  In a world where the new ACEP Clinical Policy draft is rolling back its level of recommendation for tPA, it is simply boggling to see how the other half thinks – that no frontier is too formidable for tPA.

“To Treat or Not to Treat?  Pilot Survey for Minor and Rapidly Improving Stroke”
http://www.ncbi.nlm.nih.gov/pubmed/25604250

NIHSS Scores are Not Created Equal

This is hardly news to anyone with a clinical practice, but it’s a topic rarely addressed in stroke trials – that patients with identical NIHSS can have a wide range of downstream disability.

This is a retrospective analysis of the VISTA registry, which collates non-thrombolysis acute stroke trial data, and is generally useful for identifying predictors of long-term prognosis and outcomes.  These authors used six hypothesized “profiles” of stroke syndromes with distinct constellations of disabilities, and matched a total of 10,271 patients from their database to one of the six.  Using their most disabling stroke subtype profile as reference, the authors noted three different syndromes – with median NIHSS 10, 9, and 7 – all had similar likelihood of favorable outcomes.  However, even though the NIHSS and good outcomes were similar, the disabilities and clinical profile associated with one of these cohorts translated to twice as likely to be deceased at 90 days.  In essence – similar “numbers”, but very different outcomes.

There’s nothing here usable for direct knowledge translation – but, it does hearken back to my oft-repeated statements regarding the heterogeneity of stroke syndromes, outcomes, and likelihood of benefit or harm from pharmacologic revascularization.  Quite simply, data sources such as this – and those including patients from thrombolysis trials – ought be better utilized to predict patient-specific outcomes.

“National Institutes of Health Stroke Scale Item Profiles as Predictor of Patient Outcome”
http://www.ncbi.nlm.nih.gov/pubmed/25503546

The Wholesale Revision of ACEP’s tPA Clinical Policy

ACEP has published a draft version of their new Clinical Policy statement regarding the use of IV tPA in acute ischemic stroke.  As before, the policy statement aims to answer the questions:

(1) Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?
(2) Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?

Most readers of this blog are familiar with the mild uproar the previous version caused, and this revision opens by stating “changes to the ACEP clinical policies development process have been implemented, the grading forms used to rate published research have continued to evolve, and newer research articles have been published.”  Left unsaid, in presumably a bit of diplomacy, were the conflicts of interest befouling the prior work.  Notably absent from this work is any involvement from the American Academy of Neurology.

What’s new, with a new methodology-focused rather than conflicted-expert-opinion approach?  Most obviously, there’s a new Level A recommendation – focused on the only consistent finding across all tPA trials: clinicians must consider a 7% incidence of symptomatic intracranial hemorrhage, compared with 1% in the placebo cohorts.  The previously Level A recommendation to treat within 3 hours has been downgraded to Level B.  Treatment up to 4.5 hours remains Level B.  Finally, a new Level C recommendation includes a consensus statement recommending shared decision-making between the patient and a member of the healthcare team regarding the potential benefits and harms.

Most of the reaction on Twitter has been, essentially, a declaration of victory.  And, in a sense, it is certainly a powerful statement regarding the ability for like-minded patient advocates and evidence purists to coalesce through alternative media and initiate a major change in policy.  To critique this new effort is a bit of punishing the good for lack of manifesting perfect, but there are a number of oddities worth providing feedback to the writing committee:

  • The authors provide a curious statement:  “The 2012 IV tPA clinical policy recommendation to ‘offer’ tPA to patients presenting with acute ischemic stroke within 3 hours of symptom onset was consistent with other national guidelines. Unfortunately, the essence of the term ‘offer’ may have been lost to readers and has therefore been avoided in this revision.”  I rather find “offer” a lovely term, in the sense it expresses a cooperative process for proceeding forward with a mutually agreed upon treatment strategy.  Rather than discard the term, clarification might have been reasonable.
  • They mention ATLANTIS as Class III evidence with regard to the 3-4.5 hour question.  I can see how its classification may be downgraded given the multiple protocol revisions.  That said, its inability to find a treatment benefit in spite of extensive sponsor involvement ought be a more powerful negative weighting than currently acknowledged.  Given the biases favoring the treatment group in ECASS III (given a Class II evidence label), the cumulative evidence probably does not support a Level B recommendation for the 3-4.5 hour window.
  • One of my Australian colleagues in private communication brings up a small letter from Bradley Shy, previously covered on this blog, mentioning a statistical change to ECASS III.  This statement could acknowledge this post-publication correction and its implications regarding the aforementioned imbalance between groups.
  • The authors fail to acknowledge the heterogeneity of acute ischemic stroke syndromes and patient substrates, and the utter paucity of individualized risk or benefit assessment tools – in no small consequence of the small sample sizes of the few trials rated as Class I or Class II evidence.  This is a powerful platform with which to state clinical equipoise exists for continued placebo-controlled randomization.  As we see from the endovascular trials, the acute recanalization rate of IV tPA is as low as 40% – with many patients re-occluding following completion of the infusion.  Patients need to be selected less broadly with respect to likelihood of benefit compared with supportive care.  I believe tPA helps some patients, but it should be a goal to dramatically reduce the costs and collateral damage associated with rushing to treat mimics and patients without a favorable balance of risks and benefits.  For these authors to recommend treatment in “carefully selected patients” and “shared decision-making”, more guidance should be provided – and absent the evidence to support such guidance, they should be calling for more trials!

The comment period is open until March 13, 2015.

“Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department DRAFT”
http://www.acep.org/Clinical-Policy-Comment-form-Intravenous-tPA/

Addendum 01/18/2015:
The SAEM EBM interest group is compiling comments on the evidence for feedback to the SAEM board of directors.  These are my additional comments after having had additional time to digest:

  • I agree with sICH as a Level A recommendation.  Both RCTs and observational registries tend to support such a recommendation.  Whether the pooled risk estimates are usable in knowledge translation to individual patients is less clear.  The risk of sICH is highly variable depending on individual patient substrate.  There are several risk stratification instruments described in the literature, but none are specifically recommended/endorsed/prospectively validated in large populations.
  • It is uncertain regarding the NINDS data whether their intention is to present pooled Part 1 and Part 2.  The prior clinical policy used only Part 2 for their NNT calculation, giving rise to an NNT of 8 instead of 6.  It appears they are pooling the data from both parts here.  Either is fine as long as it’s explicitly stated – the primary outcome differed, but the enrollment and eligibility should have been the same.
  • ECASS seems to be missing from their evidentiary table.  The ECASS 3-hour cohort data is available as a secondary analysis.  However, such would probably be Class III data of no real consequence for the recommendation.
  • Level B is probably an acceptable level of recommendation for tPA within the 0-3 hour window.  “Moderate clinical certainty” is reasonable, mostly on the strength of the Class III data.  However, the “systems in place to safely administer the medication” is not clearly addressed in the text.  Most of the published clinical trial and observational evidence involves acute evaluation by stroke neurology.  Does the primary stroke center certification practically replicate the conditions in which patients were enrolled in these trials/registries?  Perhaps this should be split out into a separate recommendation regarding the required setting for safe/timely/accurate administration.
  • Level B is difficult to justify for the 3 to 4.5 hour time window.  There is Class II evidence from ECASS III (downgraded due to potential for bias) demonstrating a small benefit.  The authors then cite Class III trial evidence from IST-3 and ATLANTIS in which no benefit was demonstrated.  Then, they cite the individual patient meta-analysis having similar effect size to ECASS III – because many of the patients in that subgroup come from ECASS III.  Basically, there’s only a single piece of Class II evidence and then inconsistent Class III evidence, which doesn’t meet criteria state for a Level B recommendation (1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).  
  • With both Level B recommendations, the authors also reference “carefully selected” patients, but do not cite evidentiary basis regarding how to select said patients other than listing the enrollment criteria of trials.  If the “careful selection” is strict NINDS or ECASS III criteria, this should be explicitly stated in the recommendation.
  • The Level C recommendations to have shared decision-making with patients and surrogates ought to be obvious standard medical practice, but I suppose it bears repeating given the publications regarding implied consent for tPA.  They mention two publications regarding review and development of such tools, but there is no evidence supporting their efficacy or effectiveness in use.  Frankly, calling them a starting point in such a heterogenous population is along the lines of the broken clock that’s right twice a day.  I would rather say their dependence on group-level data minimizes their practical utility, and clinician expertise will be the best tool for individual patient risk assessment.

Feel free to add your comment and I will incorporate them into my feedback to SAEM.