Category: Stroke

Better Less than More for tPA

Ah, but this is not one of those rants about the inefficacy of tPA.  This is just an amuse-bouche of a mention of an article from Stroke, regarding a line of investigation in Asian countries.

In these countries, particularly Korea and Japan, there is some substantial thought given to “low dose” tPA being just as effective, with a lower risk of intracranial hemorrhage.  Interestingly, approximately 40% of acute stroke patients in Asian countries is at this lower dose, 0.6 mg/kg compared with the typical 0.9 mg/kg.  This study is a retrospective evaluation of registry data from 13 academic stroke centers, comparing 3-month outcomes on the modified Rankin Scale.

There were, essentially, two entertaining bits from this article:

  • The rate of symptomatic ICH in centers contributing at least 100 patients during the study period ranges from 3.7% on the low side up to 13.0% on the high.
  • Given the constraints of the study, they were unable to demonstrate any reliable difference between the two doses.  In fact, as you can see from the figure below, retrospective data can be adjusted, propensity matched, or essentially tortured to show whatever advantage preferred:

Should we be using low-dose?  And why stop at 0.6 mg/kg – why not 0.3 mg/kg?  And, further down the rabbit hole, back to the ideal dose of … none.  Ah, but I kid, I kid ….

“Low-Versus Standard-Dose Alteplase for Ischemic Strokes Within 4.5 Hours: A Comparative Effectiveness and Safety Study”
http://www.ncbi.nlm.nih.gov/pubmed/26243232

Retinal Photography to Diagnose TIAs?

Our diagnostic approach to suspected cerebrovascular disease is quite simple.  Concerning neurologic findings or history?  Magnetic resonance imaging.

However, this approach is grossly inefficient – and, thus, the rise of various clinical scores such as the ABCD2 variants.  And, now, ocular fundus photography.  It generally makes sense – the retinal vessels travel through the optic nerve sheath.  They are, then, a unique window into the cerebrovascular circulation – and, accordingly, the degenerative diseases within.

It sort of works.

Looking at patients presenting to the ED with a report of focal neurologic deficits, the multivariate regression OR for cerebrovascular disease in patients with arterial narrowing in 2 segments is reported as 8.1 for stroke and 5.1 for TIA.  However, this finding was only present in 4 of 22 (18%) stroke patients and 6 of 59 (10%) TIA patients – compared with 5 of 176 (3%) patients who did not receive a diagnosis of cerebrovascular disease.

So, yes – it is probably true, as the authors claim, that finding arterial focal narrowing in the retinal vessels increases the likelihood of cerebrovascular disease (stroke and TIA).  But, clearly, the positive predictive value is still quite low, and the number of patients for whom this ocular photography adds substantially to the diagnosis is quite small.  At ~$25,000 a pop for the camera system, and the need for a specialist to screen the images for abnormalities, I do not share these authors’ enthusiasm for its eventual adoption into clinical practice.

“Ocular fundus photography of patients with focal neurologic deficits in an emergency department”
http://www.ncbi.nlm.nih.gov/pubmed/26109710

New AHA/ASA Endovascular Guidelines

How did I find out about the final publication of the new AHA/ASA Guidelines regarding endovascular intervention in acute ischemic stroke?  I received unsolicited e-mail spam from their representative at a public relations firm, gushing about the technology and offering to put me in touch with their generously available expert.

Before getting into the content, the standard housekeeping exercise regarding declared financial conflicts of interest:

  • Dr. Powers: None
  • Dr. Derdeyn: Microvention, Penumbra, SILK Road, Pulse Therapeutics
  • Dr. Biller: None
  • Dr. Coffey: None
  • Dr. Hoh: None
  • Dr. Jauch: Covidien, Genentech, Penumbra, Stryker
  • Dr. K. Johnston: Roche/Genentech
  • Dr. S. Johnston: None
  • Dr. Khalessi: Covidien, Microvention, Penumbra, Sequent, Codman, Stryker
  • Dr. Kidwell: None
  • Dr. Meschia: None
  • Dr. Ovbiagele: None
  • Dr. Yavagal: Covidien/Medtronic, Penumbra

Yes, Virginia, despite the worldwide availability of methodologists and clinicians to review evidence for guidelines, the AHA/ASA were unable to compose such content absent individuals with professional and financial relationships to the manufacturers of the products involved.  Another sad failure regarding the Institute of Medicine’s Guidelines We Can Trust.

So, what’s wrong with these guidelines?  I’ve written and published multiple times regarding endovascular intervention, and it’s a therapy I’m excited about.  For once, the theory and the practice seem to demonstrably align.  The new stent retrievers seem to substantially benefit patients with viable tissue behind a clot – whether because of collateral circulation, retrograde flow, or semi-permeable occlusion – and have the clot safely removed in a timely fashion.

But, that isn’t everyone.  The most successful trials – ESCAPE, EXTEND-IA, and SWIFT-PRIME – were all designed to intervene on a narrow population with salvageable tissue.  The less successful, but still positive, trials – REVASCAT and MR-CLEAN – generally intervened based only on broadly eligible angiographic occlusions.  Such a strategy will definitely catch the few patients with salvageable tissue, but also involves significant resource utilization and procedural risk conferred upon those without the possibility of benefit.

However, that’s what these guidelines suggest – to treat all-comers presenting within six hours, discarding the use of tissue-based criteria for intervention.  The benefit to the corporations involved is obvious, as routine angiography – let alone rapid perfusion calculation – is not widespread.  Without the broadest possible criteria, many centers might not refer patients for intervention.  Given the choice between maximizing yield of this intervention and generating profits for their financial and professional affiliates, the authors of this guideline have chosen the latter.

Not only that, these authors give this recommendation the strongest possible Class I and Level A qualifiers.  The body of the text states this is a result of the findings of the five aforementioned trials published at the time this was drafted.  Unfortunately, from just a simple methodologic standpoint, the authors have developed complete amnesia regarding the entire prior body of negative evidence regarding endovascular intervention – nor acknowledged the open-label nature of these trials stopped early, nor other threats to bias.

So, yet again – from the folks who gave us flawed tPA guidelines and “quality measures” – a guideline we can’t trust.  The Society for Academic Emergency Medicine was solicited to endorse this guideline several months ago, and I was involved in the review process at that time.  Unfortunately, none of the concerns expressed at that time appear to have been addressed – and as such, SAEM is not included among the professional societies endorsing this guideline.

Endovascular therapy is coming.  And, unfortunately, it is certainly going to be coming to many more than for whom appropriate.

“2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment”
http://m.stroke.ahajournals.org/content/early/2015/06/26/STR.0000000000000074.full.pdf

The New, Improved, ACEP Clinical Policy for tPA in Stroke

Released with minimal fanfare, approved by the ACEP Board of Directors on June 24th, the revised ACEP Clinical Policy regarding the use of TPA for acute ischemic stroke has gone final.

It is, of course, a vast improvement over the 2012 version – but has, unfortunately, changed for the worse since the draft was posted.

The highlights:

  • The Level A suggestion to consider the risk of ICH with tPA administration has been eliminated.  It has been moved, nonsensically into the Level B recommendations for offering tPA – when, frankly, it’s the only consistent finding across all the evidence.
  • The Level B recommendation in which tPA “may be given” within 3 hours has been strengthened to “should be offered and may be given”.  Obviously, a profound difference.
  • The Level B recommendation for 3-4.5 hours remains unchanged, based on only one flawed piece of Class II evidence (ECASS III), and conflicting Class III evidence (ATLANTIS, IST-3, meta-analyses).
  • The Level C recommendation to engage in shared decision-making now states “when feasible”, which is obviously open to interpretation.
  • No further clarification of “carefully selected patients” or “systems … in place to safely administer the medication” is provided.

Some wins, some losses.  Obviously, the shared decision-making supporting any “offer” of tPA can be very different, depending on an individual clinicians’ interpretation of the evidence – and it is nice to see the prior COI-infested husk of rotten guidelines finally, officially, tossed on the compost heap.  Let us hope (irrationally, of course) the efforts underway in the United Kingdom spur further, independent, investigation with which to better understand and individualize the risks and benefits of treatment with tPA.

“Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department”
http://www.acep.org/workarea/DownloadAsset.aspx?id=102373

DIAS-3 – Desmoteplase Fails in the Extended Time Window

It seems to be the stroke neurologists’ greatest lament – the restricted time windows for tPA, either 3 or 4.5 hours, excluding so many patients from receiving the blessing of thrombolysis.  There have been failed trials in the past in extended time windows, and, even, failed trials in the 3-5h time window.  But, this is desmoteplase, and it is more fibrin specific than alteplase – and this follows up DIAS-2, which seemed to suggest benefit in patients with demonstrated arterial conclusion on vascular imaging.

It is, sadly, negative by the primary outcome of 90-day Rankin score (mRS 0-2), adding another tick mark to the list of failed contemporary trials for systemic thrombolysis.  Safety outcomes, mercifully for the patients involved, were similar, with low rates of neurologic worsening associated with intracranial hemorrhage in each cohort.

The authors, as before, find and focus on a single positive subgroup: patients with ischemic injury volume of less than 25mL on MRI.  There was, interestingly, no positive effect noted for patients whose ischemic injury volume was less than 25mL on CT – and the authors had no specific explanation for the discrepancy.  However, given the recent successful endovascular trials, it is quite reasonable to suggest an imaging-based, tissue-salvage model is more appropriate than the simplistic time-based model suggested by NINDS.  Unfortunately, tissue salvage is dependent upon recanalization – and rates were not significantly different between cohorts, 49% with desmoteplase vs. 42% with placebo.  This is the persistent elephant neurologists fail to acknowledge – that systemic thrombolysis simply rarely works as advertised – greatly diminishing any possible beneficial effect.

The conflict-of-interest statement falls on what probably would have once been considered the extreme side, but now is tragically routine:

The funder was involved in the study design, data collection, data analysis, and data interpretation. Two employees of the funder provided medical writing assistance in the editing of the report. The corresponding author had full access to all study data; all other authors without funder affiliation had access to study data via the corresponding author and authors with funder affiliation had full access to all study data.

Interestingly, review of the ClinicalTrials.gov registration indicates the study was initially planned in 2008 to enroll 320 patients, with an end date in 2010.  In 2010, the planned enrollment was increased to 400, and the study ultimately enrolled 492.  Given the COI involved, it reasonable to suggest the funder was involved in ongoing analysis of the results with the intention of stopping the study at the precise moment a positive outcome – or ultimate futility – was detected.  Despite the best efforts of Jeff Drazen and the NEJM to downplay potential distortions secondary to funding sources, clearly, our vigilance for such likely scientific misconduct should not be diminished.

“Safety and efficacy of desmoteplase given 3–9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial”
http://www.ncbi.nlm.nih.gov/pubmed/25937443

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

Attempting Decision-Support For tPA

As I’ve wondered many times before – given the theoretical narrow therapeutic window for tPA in stroke, paired with the heterogenous patient substrate and disease process – why do we consent all patients similarly?  Why do we not provide a more individualized risk/benefit prediction?

Part of the answer is derived from money & politics – there’s no profit in carefully selecting patients for an expensive therapy.  Another part of the answer is the reliability of the evidence base.  And, finally, the last part of the answer is the knowledge translation bit – how can physicians be expected to perform complex multivariate risk-stratification and communicate such information to a layperson in the acute setting?

In this paper, these authors describe the development process of an iPad application specifically designed for pictoral display of individualized risk/benefit for tPA administration in acute ischemic stroke.  Based on time from onset to treatment, age, gender, medical history, NIHSS, weight, and blood pressure, manual entry of these variables into the software provides individualized information regarding outcomes given treatment or non-treatment.

Unfortunately, the prediction instrument – S-TIPI – is based on: NINDS, ECASS II, and ATLANTIS.  Thus, as you might expect, in the most commonly used time frame of 0-3 hours, the outcomes essentially approximate NINDS.  The authors mention they used the UK portion of the Safe Implementation of Thrombolysis in Stroke database and the Virtual International Stroke Trials Archive to refine their calculations, but do not delve into a discussion of predictive accuracy.  Of note, a previous article describing recalibration of S-TIPI indicated an AUC for prediction of only 0.754 to 0.766 – but no such uncertainty, nor their narrowly derived limited data set, are described in this paper.

Regardless, such “precision medicine” decision instruments – for both this and other applications – are of great importance in guiding complex decision-making.  This paper is basically a “check out what we made” piece of literature by a group of authors who will sell you the end result as a product, but it is still an important effort from which to recognize and build.

“Development of a computerised decision aid for thrombolysis in acute stroke care”
http://www.ncbi.nlm.nih.gov/pubmed/25889696

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

Again With the Claim tPA is “Safe” in Mild Strokes

In yet another exercise in asking the wrong questions, these authors put forth a rather great deal of effort to regurgitate a vast quantity of mostly meaningless data.

Neurologists, generally those well-supported by Genentech and Boehringer Ingelheim (as in this article), are keen to expand the use of tPA beyond the license criteria.  One of the easiest targets is the giant cohort of stroke patients excluded from treatment for low NIHSS.  In some respects, it seems reasonable to discard an ordinal cut-off in a measure of stroke severity having a non-linear relationship with disability.  But, when media coverage describes an expansion of tPA to mild stroke patients as “saving hundreds of millions of dollars” or “having no downside”, even the hypothetical best intentions have clearly gone awry.

This is a retrospective review of the Get With the Guidelines-Stroke registry, a voluntary, prospective quality improvement project used by hospitals in the U.S.  Between 2010 and 2012, 7,621 patients were treated with IV tPA for AIS having an NIHSS of 5 or less, with 5,910 having data for analysis.  Ranging from 192 patients with an NIHSS to 0 to 1,800 having NIHSS of 5, treatment complications were fairly consistent: 1.3% died, 1.8% suffered sICH, 0.2% suffered serious systemic hemorrhage, and 1.8% suffered other serious complications (e.g., angioedema).

So, of course, for a treatment with no demonstrated efficacy in this population, the authors conclude a number-needed-to-harm somewhere between 30 and 50 “provide[s] reassurance about the safety of IV rtPA in patients with low NIHSS scores”.

Interestingly, this data is essentially an update of the authors’ prior work, published using the 2003 to 2009 GTWG-Stroke registry data.  That publication provided a helpful data supplement comparing outcomes of tPA-treated patients with non-tPA-treated patients with NIHSS 5 or less.  Within the limitations of such a comparison, tPA treatment was associated with significantly increased odds of death, decreased discharges to home, and decreased ambulation at discharge.  The authors have in no way muddled this article with such negativity, nor did they perform any sort of gross comparison between the ambulatory and independence outcomes in the present study with the prior, non-treated population – as they are essentially identical.

But, when you’re fed free money from your sponsors, including free airfare to Chicago, why report or suggest anything that might disrupt the narrative?

“Outcomes in Mild Acute Ischemic Stroke Treated With Intravenous Thrombolysis: A Retrospective Analysis of the Get With the Guidelines–Stroke Registry”
http://www.ncbi.nlm.nih.gov/pubmed/25642650

A Laughable tPA “Systematic Review”

Over 200,000 physicians belong to the American Medical Association.  The Journal, therefore, of this Association has a significant audience and a long tradition.  Continuing Medical Education inserts in JAMA may represent the basic education of many new developments for general practitioners.

Unfortunately, the authors of this most recent CME portion seem to require their own education on the conduct of a “systematic review”.

A properly performed systematic review utilizes a precise, replicable, well-described search strategy with which to canvass the evidence for synthesis.  The assembled evidence is then evaluated based on pre-specified criteria for inclusion or exclusion.  The end-result, hopefully, is a knowledge translation document based on the entire scope of published literature, accounting for controversy and irregularity in the context of a larger summary.

These authors perform a systematic review on “acute stroke intervention”.  They identify and review 145 abstracts utilizing multiple combinations of MeSH terms and synonyms for “brain ischemia/drug therapy, stroke drug/therapy, tissue plasminogen activator, fibrinolytic agents, endovascular procedures, thrombectomy, time factors, emergency service, treatment outcome, multicenter study, and randomized controlled trial”.  A massive undertaking, to be sure – considering these authors are also including intra-arterial and mechanical therapy in their review.

Yet, as indicated in their evidence review chart in the supplement, this strategy managed to identify only 17 RCTs – in the whole of systemic and endovascular therapy.  As an example for comparison, the latest Cochrane Review of thrombolytics for acute ischemic stroke included 27 trials of fibrinolytic agents alone.  And, as covered in their text and cited in their References, the RCT evidence regarding systemic therapy for acute stroke consists of: NINDS and ECASS III.

That’s it.

No MAST-E, MAST-I, or ASK.  No mention of the smaller imaging-guided trials, EPITHET, DEDAS, DIAS, or DIAS II.  Or, even excluding non-tPA trials, no ECASS, ECASS II, ATLANTIS, or, even the largest of flawed acute stroke trials, IST-3.  And, even with such limited coverage, certainly no mention of any of the controversy over imbalances in NINDS, nor flaws in ECASS III pertaining to tPA’s persistent non-approval by the FDA for the 3-4.5 hour time window.

If this were simply a commentary for the lay press regarding the bare minimum highlights of the last 20 years of stroke treatment, perhaps this would suffice.  And, frankly, these authors do much better regarding their reporting on the recent endovascular trials.  But, a CME publication in a prominent medical journal failing to address 90% of the evidence on a particular topic – yet calling itself a “systematic review” – is retraction-worthy.

“Acute Stroke Intervention – A Systematic Review”
http://jama.jamanetwork.com/article.aspx?articleid=2247149