Category: Stroke

It’s Stroke Week Again!

Discovery Channel had Shark Week.  Around Emergency Literature of Note Headquarters, we do Stroke Week.

Why?  Because, from a methodologic standpoint, acute stroke care is the gift that keeps on giving.  This week, we will see randomized-controlled trials stopped for “loss of equipoise”, a few authors who are still working out how to conduct a systematic review, and more practice-changing conclusions drawn from retrospective registry data.

As we noted a couple weeks ago, there were three major endovascular trials presented in early February – ESCAPE, EXTEND-IA, and SWIFT-PRIME.  ESCAPE and EXTEND-IA were simultaneously published in the New England Journal of Medicine.  Now, SWIFT-PRIME has reached final publication.  These trials are hailed as a sort of second-coming of the messiah for the exiles wandering in the wilderness since PROACT-II.

And, now, interestingly, a fourth trial is presented – simultaneously published along with presentation at the European Stroke conference.  This is REVASCAT, yet another stent retriever trial funded by an unrestricted grant from Covidien, the manufacturers of the Solitaire device.  And, I can tell you Covidien saved themselves a lot of money in this trial – because it was planned to enroll 692 patients, and was terminated after 206.

Why was it terminated?  Not, as the other trials were, due to having met pre-specified efficacy criteria.  This trial was stopped because of “loss of equipoise”, following presentation of the other trials.  This is, effectively, the equivalent of stopping your moon landing program because the other side got there first, sitting around glumly shuffling papers.  But, more data is still important – and this data is important because it throws a little bit of cold water on the other trials.

SWIFT-PRIME, for example – mRS 0-2 in 60% of the endovascular intervention cohort, compared with 35% of the tPA-only cohort.  REVASCAT – mRS 0-2 in 44% of the endovascular cohort, compared with 28% of the tPA-only cohort.  25% treatment difference versus 16% treatment difference.  SWIFT-PRIME – 12% mortality in the endovascular cohort, compared with 26% mortality with usual care.  REVASCAT – 18% mortality in the endovascular cohort compared with 15%.

What’s different?  Where the previously presented trials used strict imaging criteria for small infarct cores and good collateral circulation, REVASCAT simply included all patients with low ASPECTS scores and proximal vascular occlusions.  This is, then, more akin to MR-CLEAN or ICARO-3, in which the benefit is attenuated substantially if the status of the underlying tissue is not fully appreciated.

The lesson from this should be clear – imaging criteria requiring salvageable tissue as result of collateral flow provide maximum yield in reducing the number of endovascular procedures performed with low or no chance of benefit.  Whether these lessons are heeded, I remain highly skeptical.

The other lesson: when you’re hot, you’re hot, and even lukewarm half-raw results can still get you into NEJM.

“Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1503780

“Stent-Retriever Thrombectomy after Intravenous t-PA vs. t-PA Alone in Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1415061

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

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

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

Ceftriaxone: It’s Not For Stroke

Negative trials are just as important – if not moreso – than positive trials.  Without negative trials, well-meaning clinicians continue with unproven and unverified treatments, incurring unnecessary costs and exposing patients to unneeded potential adverse effects.

This prospective trial of 2,550 patients randomized patients post-stroke to four days of prophylactic ceftriaxone versus no treatment, using an open-label, masked endpoint design.  The theory – some of the mortality and disability post-stroke may be in excess as result of infectious (primarily respiratory) complications.  The fact – no.  There was no difference in functional outcome at any modified Rankin Score ordinal cut-off, nor mortality.  There were actually not fewer cases of pneumonia in the ceftriaxone group, but urinary tract infections were significantly suppressed.  Clostridium difficile infection occurred only in two cases, both in the ceftriaxone group.

As a random aside, the median NIHSS in this trial was 5 – and 37% of patients achieved mRS 0-1.  This is rather surprisingly low, considering the SITS-MOST cohort and pooled placebo groups from RCTs with median NIHSS’ ~12 had achieved mRS 0-1 in 38% and 33% of the time, respectively.  A window into the lack of generalizability of the thrombolysis RCTs?  Perhaps – or just a curiosity.

Oh, but, back to the point – it does not appear to have clinical utility to routine use ceftriaxone as antibiotic prophylaxis after acute ischemic stroke.

“The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial”
http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)62456-9.pdf

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.

Endovascular Therapy, Unproven Efficacy, Unproven Effectiveness

With the publication of MR-CLEAN two days ago, the medical world (especially Covidien, Stryker, and Penumbra) is ready to throw out all previous neutral trials – MR-RESCUE, SYNTHESIS, IMS-3 – and rush headlong into endovascular therapy for acute ischemic stroke as a new standard of care.

Nonsense, you say?  Not when financial and professional conflicts-of-interest coordinate to drown out the skeptics.

And, frankly, the reality is – despite trials failing to demonstrate benefit, endovascular therapy is already in widespread use.  The underlying tissue-reperfusion hypothesis upon which thrombolytic therapy is predicated is too compelling to wait for proof of efficacy or effectiveness.  Alas.

This is ICARO-3, essentially an ongoing prospective registry of patients considered by experts as optimal candidates for endovascular interventions.  These are all proximal internal carotid artery occlusions, having the among the least favorable rates of recanalization with IV tPA alone.  These authors obtained data on 324 cases between 2010 and 2013 receiving endovascular therapy and 324 matched controls (including 253 from the original ICARO study).  The endovascular cohort included a distribution of patients who received intra-arterial lysis, mechanical retrieval, systemic thrombolysis, or a combination of those treatments, while the tPA cohort received systemic thrombolysis alone.

Patients were generally well-matched on baseline characteristics, with an overall median NIHSS of the entire cohort of 16.  Ultimately, 18.2% of the IV tPA-only cohort had an mRS 0-1 at three months, compared with 20.7% of the endovascular cohort, and OR of 1.17 (95% CI 0.79-1.73).  However, 37% of the endovascular cohort experienced intracranial bleeding of which 6% was fatal, compared with 17.3% and 2.2% in the tPA-only cohort.  In summary, the outcomes – both positive and negative – were a wash.  The authors try to splice out an adjusted subgroup of specific types of endovascular interventions with improved outcomes compared with controls, but these statistical calisthenics are best left unmentioned given their limited validity.

So, until MR-CLEAN, all the randomized trials for efficacy have been neutral.  ICARO-3, a real-world effectiveness observation – also neutral.

Is it too late to derail the bandwagon?

“Intravenous thrombolysis or endovascular therapy for acute ischemic stroke associated with cervical internal carotid artery occlusion: the ICARO-3 study”
http://www.ncbi.nlm.nih.gov/pubmed/25451851

MR-CLEAN & the New Golden Age

I, among many others, have been highly skeptical of thrombolytic therapy and its role in the treatment of acute ischemic stroke.  As has been well-documented, a few trials were positive, many were neutral, and a few were stopped early for harm or futility.  To most of us, this indicates a therapy for whom only a small subset of those treated are ideal candidates for benefit, and the margin between benefit and harm is razor thin.

In my previous posts, I’ve sighed wistfully at the hope of The Next Big Thing in stroke treatment – local endovascular therapy, akin to percutaneous coronary intervention.  However, each major endovascular trial published in the New England Journal last year failed to demonstrate benefit.

MR-CLEAN is different.  MR-CLEAN is rather unambiguously positive.  To be zero or minimally disabled?  The endovascular intervention is favored 12% to 6%.  “Functionally independent”, a modified Rankin Scale of 0-2, favors endovascular intervention 33% to 19%.  A number needed to treat of, apparently, ~8 for independence is nothing to scoff at.

But why?  It’s very similar to IMS-3, which was stopped early due to futility.  Patients are about the same age.  The comparator – usual care, typically tPA – is the same.  Median NIHSS is about the same.  The differences are quite subtle.  Patients were randomized earlier in IMS-3 compared with MR-CLEAN, with the implication IMS-3 includes patients whose natural course was superior, whereas MR-CLEAN enrolled “non-responders”.  The other difference, and the one you’ll hear by far the most frequently, is that MR-CLEAN utilized modern stent retrievers, rather than such killing machines as the MERCI device.  Newer, as you’ve always been taught, is better.

But, clearly, there’s something else we simply cannot splice out of these data.  Patients in MR-CLEAN did awful.  Recall NINDS, where a tPA cohort with a median NIHSS of 14 resulted in 39% attaining mRS 0-1.  In IMS-3, intravenous tPA with a median NIHSS 16 resulted in 26% mRS 0-1.  In MR-CLEAN, intravenous tPA with a median NIHSS of 18 resulted in 6% mRS 0-1.  Patients in MR-CLEAN did recanalize at a greater rate than those in IMS-3, 58% vs. 23-44%, owing to the improved performance of modern retrievers.  In a world where definitively opening the vessel, where reperfusion means time=brain, this makes sense.  But, like NINDS, the positive results do not seem so much to result from the intervention, but rather from the control group simply doing unwell.

As the embargo lifts, I’m sure this post is one of a tiny minority wondering if this is fool’s gold.  If you think of p-values like likelihood ratios, as initially intended, the presence of multiple prior neutral evaluations makes the bar for success that much higher in follow-up trials.  These are excellent results, results I’d like to believe in, but the totality of evidence to date requires they be validated.

I wholeheartedly expect they will not.  Prepare for the full onslaught of hype regarding endovascular therapy for stroke.

“A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1411587