Category: Neurology

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

The “Golden Hour” of tPA

As part of every Genentech-sponsored CME or medical school curriculum presentation on thrombolysis in acute ischemic stroke, you see a graph like this:

This is the “time is brain” mantra, where every supposed passing second without flow destroys another mass quantity of brain cells.  The theory: on the edge of the infarcted brain tissue, there remains yet a thin rim of cells between vascular territories, just barely hanging on.  Timely reperfusion saves these cells – and tPA increases recanalization rates incrementally beyond control, in certain patients, and in certain vessels.  However, again, in certain patients, and in certain vessels, the tPA results in serious intracranial bleeding.  This risk/benefit trade-off remains a cornerstone controversy in Emergency Medicine and Neurology, owing to the paucity of unbiased clinical trial data.

But, most patients eligible for tPA arrive at the hospital far at the low end of the curve – where the time-dependent effects are weakening.  As such, the new magic is to take the tPA to the patient – delivering thrombolysis in a van down by the river.  The STEMO from Germany, and its PHANTOM-S project, paved the way for other “mobile stroke units”.  This report aims to evaluate the “Golden Hour” of stroke thrombolysis – patients receiving tPA within 1-hour of symptom onset – where the time-is-brain ought wholeheartedly manifest.

Ah, but, so – such an effect, unfortunately, was not conclusively observed.  Comparing 78 patients who received tPA in fewer than 60 minutes (median 50 minutes) with 451 patients receiving tPA in greater than 60 minutes (median 105 minutes), these data support no useful conclusions regarding the effectiveness of such timely delivery.  The unadjusted analysis shows no difference in outcomes between groups, but, alas, the groups are grossly imbalanced.  Adjusted analyses, in their crude adjustments, tend towards benefit in the <60 minute cohort, but such post-hoc comparisons can only be considered exploratory.  Of course, the accompanying editorial “Prehospital Thrombolysis for Stroke: An Idea Whose Golden Hour Has Arrived” cleanly ignores the adjusted nature of these data, and definitively endorses the observed benefit.

Considering pre-hospital thrombolysis provides such excellent opportunity to truly test the time-is-brain hypothesis, it’s a shame its proponents are not taking such an uncritical view of the opportunity for study.

“Effects of Golden Hour Thrombolysis: A Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke (PHANTOM-S) Substudy”
http://www.ncbi.nlm.nih.gov/pubmed/25402214

For tPA, Is Delusion the Standard of Care?

Yet again, the tPA apologists dip into their bag of registry data in an attempt to defend tPA – and end up contradicting themselves.

In 2009, neurologists in India published a retrospective case series examining the outcomes following tPA at their institution.  Specifically, they divided up the cases between those with arterial occlusion present on CT angiogram of the cerebral vessels, and those with no demonstrated arterial occlusion.  For patients with demonstrated occlusion, there were significant differences in early NIHSS improvement favoring tPA, but no long term mRS improvements.  Conversely, there were 119 without occlusion present – and the early NIHSS improvement and late mRS improvement outcomes were similar.  There were, however, substantial baseline differences between those receiving tPA and those who did not – and retrospective studies are confounded by many biases – but there was at least a suggestion that some stroke subtypes might not benefit from tPA.

Clearly, that did not sit well with the authors of this study, a handful of whom are paid representatives of Boehringer Ingelheim.  They performed their own retrospective review of a multi-center registry to evaluate outcomes of patients without arterial occlusion demonstrated on initial angiography, but definitive acute stroke seen on follow-up MRI.  They also further subdivided stroke subtypes into lacunar (subcortical, thalamic, and pontine infarct <20mm) vs. non-lacunar (all others).

They identified 154 non-lacunar strokes, 49 of whom underwent thrombolysis, and 102 lacunar strokes, 54 of whom underwent thrombolysis.  Outcomes favored tPA for non-lacunar stroke syndromes, with 51% of tPA patients mRS 0-1 at 90 days, compared with 30% for those who did not receive tPA.  Symptomatic intracranial hemorrhage occurred in 6.1% of tPA patients, compared with 1% without.  Lacunar strokes, however, had identical 90 day mRS outcomes – 65% vs. 63%.  For lacunar strokes, sICH occured in 3.7% of tPA patients vs. 0% without.  The authors still try to statistically adjust their way out of this equivalency for the primary outcome – but fail.

So, again, this is a retrospective study confounded by many biases.  However, the authors have nicely demonstrated support for a hypothesis some stroke subtypes – particularly those for whom no arterial occlusion is demonstrated on angiography – might not benefit from tPA.  Thus, the conclusion:

“In conclusion, this retrospective study demonstrates the efficacy of intravenous thrombolysis in patients with ischemic stroke who have no radiographically demonstrated arterial occlusion at presentation. Both subgroups, nonlacunar and lacunar strokes, were found to have had better clinical outcome after receiving r-tPA.”

Or, the opposite of what their data suggests.

Is it really so impossible conceive tPA might not be magical?

“Thrombolysis in Ischemic Stroke Without Arterial Occlusion at Presentation”

United Kingdom Revisiting Safety of tPA

This odd and tragic saga continues: nearly 20 years after the original NINDS publication, we’re still going around and around with re-reviews of the same evidence.  The recent news of this past week is the Medicines and Healthcare products Regulatory Agency in the United Kingdom will set up an expert panel to reevaluate the evidence in support of tPA for stroke.  In light of a recent positive Cochrane Review, a positive individual patient meta-analysis, and a paucity of substantial new data – I cannot imagine what new insight will be uncovered.

This seems to have been brought about by correspondence, written by a British stroke neurologist, in The Lancet, describing the same series of arguments skeptics have been making for the last decade and a half.  There are concerns over inadequate blinding of investigators, noting the alteplase infusion may be visually different from placebo, or that patients treated with alteplase possibly had observable minor bleeds from venipuncture sites.  The manufacturer-sponsored nature of ECASS, ECASS II, and ECASS III is again cited, along with baseline imbalance regarding prior strokes favoring the treatment group in ECASS III.  ATLANTIS is also mentioned as a negative trial, stopped early by interim futility analysis.  He further mentions the lack of difference between <3h and 3-4.5h windows in observational registries, suggesting the underlying time-dependent hypothesis behind treatment with alteplase is flawed.  And, most interestingly, he provides a funnel plot of outcomes by treatment center from NINDS, suggesting certain centers suspiciously had disproportionately positive findings.

Again, these are many of the same arguments made by other  experts in their critiques of the evidence behind thrombolysis for stroke.  As such, the responses – headlined by Peter Sandercock and Joanna Wardlaw – provide some of the same rebuttals as previously seen.  Essentially, what it boils down to – again – is you either trust the data, or you don’t.  And, given the suppressed evidence associated with Boehringer Ingelheim’s dabigatran product, not trusting the data remains a reasonable standpoint.

Whether the the MHRA enquiry will change any regulatory statutes is another issue entirely, and Ian Hudson states there will be a fair re-appraisal.  However, Prof. Simon Brown points us to this interesting blog entry covering Mr. Hudson’s prior time at GlaxoSmithKline.  This journalistic endeavor covers his potential role in overlooked safety concerns regarding paroxetine, as well as other conflicts of interest, and implies the enquiry is unlikely to be truly balanced.

Not to sound like a broken record, but only one thing will settle this debate, once and for all – a large, multi-center, randomized trial conducted independently from the manufacturers of alteplase and otherwise biased institutions.  And, since the chance of that happening is basically nil – I imagine another decade from now, we’ll still be picking apart stroke research and debating the quality of the evidence.

“Questions about authorisation of alteplase for ischaemic stroke”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61385-4/fulltext

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61386-6/fulltext

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61387-8/fulltext

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61388-X/fulltext

Just Another Advertisement for tPA

As with last week’s coverage of the updated Cochrane Systematic Review for tPA in acute ischemic stroke, the key question is: what’s new?

The first pooled meta-analysis, published in The Lancet in 2004, included NINDS, ECASS I, ECASS II, and ATLANTIS.  It was subsequently updated in 2010 to add ECASS III and EPITHET.  Now, these authors have decided to add IST-3.

I am actually a huge fan of individual-patient meta-analyses.  Depending on the data availability, the similarity of trial protocols, and other issues associated with heterogeneity, this is the gold-standard for aggregating data and increasing power.  Individual-patient analyses also allow for more reliable exploration of subgroup effects not otherwise possible through regular meta-analyses or systematic reviews.

But, at the crux of it, a meta-analysis is only as good as the included trials – and this is a topic much debated over the last twenty years.  Entertainingly, the 2014 publication includes this bland statement:

Role of the funding source 

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data and responsibility for the decision to submit for publication.

Yes, the funding source had nothing to do with the study design, excepting all the folks receiving speaker fees and honoraria – and the fact the original idea and refinements to the approach were contributed by one of the authors who is an employee Boehringer Ingelheim:

KRL has received speaker fees from and has served on the data monitoring committee of trials for Boehringer Ingelheim; his department has received research grant support from Genentech.  GA has received research grant support from Lundbeck, fees for consultancy and advisory board membership from Lundbeck, Covidien, Codman, and Genentech, fees for acting as an expert witness, and owns stock in iSchemaView. EB is employed by Boehringer Ingelheim. SD has received honoraria from Boehringer Ingelheim, EVER Pharma, and Sanofi and has received fees for consultancy and advisory board membership from Boehringer Ingelheim and Sanofi. GD has received research grant support from the NHMRC (Australia) and honoraria from Pfizer and Bristol-Myers Squibb. JG has received fees for consultancy and advisory board membership from Lundbeck. RvK has received speaker fees and honoraria from Penumbra and Lundbeck. RIL has received honoraria from Boehringer Ingelheim. JMO has received speaker fees from Boehringer Ingelheim. MP has received travel support from Boehringer Ingelheim. BT has received honoraria from Pfizer.  DT has received speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim and Bayer.  JW has received research grant support from the UK Medical Research Council and from Boehringer Ingelheim to the University of Edinburgh for a research scanner bought more than 10 years ago. WW has received research grant support from the UK Medical Research Council. PS has received honoraria for lectures which were paid to the department from Boehringer Ingelheim. KT has received research grant support from the Ministry of Health, Labour, and Welfare of Japan, and speaker fees from Mitsubishi Tanabe Pharma.  WH has received research grant support from Boehringer Ingelheim, and speaker fees and fees for consultancy and advisory board membership from Boehringer Ingelheim.

The same level of COI was present in previous versions – including employees of the sponsor as authors – but, interestingly, at least the 2004 version explicitly acknowledges a critical issue:

Role of the funding source 

For the ATLANTIS trials, Genentech provided full support for the study and Genentech employees participated to some extent in study design, data collection, data analysis, and data interpretation, writing of the report, and in the decision to submit the manuscript for publication. For the ECASS trials, Boehringer Ingelheim provided full support. Employees of Boehringer Ingelheim participated in study design, in data collection, data analysis, data interpretation, writing of the report, and in the decision to submit the report for publication.

Nothing has changed.  If you trusted the data then, you trust the data now – and vice-versa.

So, what is new?  If anything, what’s new is worse than preceded it.  The authors have nearly doubled the cohort for analysis – by the inclusion of a decade-long trial crippled by the bias introduced by an open-label, mostly unblinded design.  Despite the massive resources invested in conducting it, unfortunately, IST-3 is too flawed for inclusion – due to the unfortunate likelihood any small positive signals regarding tPA are certain to be exaggerated.  And, simply put, that’s where the astute reader ought to stop reading this publication.  There’s no point in trying to interpret their results, to fuss over the heterogeneity between trials, missing baseline characteristics for their many subgroup analysis, or whether the trials stopped early for harm or futility – ATLANTIS – are properly acknowledged.  The authors also omit several planned secondary analyses described in their statistical protocol – although, considering the garbage-in/garbage-out nature of this work, it’s of debatable importance.

The last decade of prospective research – ECASS III and IST-3 – has done nothing but degrade the quality of evidence describing tPA in acute ischemic stroke.  If there is, indeed, anyone left on the fence regarding the pro/con tPA debate, this effort ought move the needle zero to none.  Very early treatment with tPA probably benefits a properly selected subset of patients with acute ischemic stroke.  The rest – whether increasing age, high-or-low NIHSS, specific stroke syndromes, or time-dependent factors – have much smaller, if any, chance of benefit exceeding chance of harm.  Until we have unbiased evidence, we’ll never truly know how to best select patients for this therapy – and neurologists will continue to lament low treatment rates, while Emergency Physicians continue to reject pro-tPA clinical policies.  Only new, independent data has a chance to substantially change our approach to acute ischemic stroke.

“Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60584-5/abstract

A Moratorium on Steroids for TBI

A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.

In 2004 the CRASH trial examining the efficacy of steroids for acute traumatic brain injury (TBI) was published in The Lancet.  This massive trial included over 10,000 patients was stopped prematurely because of an increased mortality in the patients who received corticosteroids. This should have definitively closed the book on such a therapy.  Despite this damning evidence, it appears all one has to do to make this question relevant again is to devise a disease-oriented endpoint with plausible clinical relevance and test it using a sample size too small to differentiate these harms from the surrounding noise of statistical chance.

Authors of the recently published Corti-TC trial did just this. Asehnoune et al examined the effect of the combination of hydrocortisone and fludrocortisone for the prevention of hopsital-acquired pneumonia (HAP) in patients with severe TBI. This is not the authors first foray into the efficacy of steroids for TBI. Their original trial was published in JAMA in 2011 and examined the effects of hydrocortisone to prevent HAP in patients having experienced poly-trauma. In this initial trial, about half the 149 patients randomized to either hydrocortisone or placebo suffered a severe TBI. The authors found that 35.6% of the patients in the active treatment arm developed HAP compared to 51.3% in the placebo group. This difference was seen exclusively in the subgroup of patients with TBI.  Thus the authors set out to validate these findings by solely examining patients suffering from acute TBI. As a harbinger of things to come, the authors justified the 3% increase in mortality as statistical chance, since it failed to reach statistical significance due to the small sample size.

In what essentially is a validation cohort the Corti-TC  trial was devised. Patients were randomized to either a 10 day course of both hydrocortisone and fludrocortisone or equivalent placebos. Cortisol levels were drawn before treatment was initiated, and in those found to be adrenally competent treatment was stopped. Once again the authors’ primary endpoint was the 28-day incidence of HAP as defined by a new infiltrate on chest x-ray with at least two of the following criteria; a temperature >38°C, leucocytosis >12 000 cells per mL, leucopenia <4000 cells per mL, or purulent pulmonary secretions.

Corti-TC demonstrated a similar difference in rates of HAP in patients given steroids vs those who received the placebo. Specifically 45% of the patients in the steroid group compared to 53% in the control group developed HAP over the first 28-days.  Although this difference did not reach statistical significance due to a lower than anticipated overall incidence of HAP, a relevant divergence between the active and control groups is evident. This difference remained consistent whether or not patients were found to have adrenal deficiency, indicating that cortisol levels do not predict a subset of patients who will benefit from steroids. Of concern is the 2% absolute increase in mortality of patients treated with steroids. This difference was observed primarily in the subset of patients later found to be adrenally intact. The authors once again justify this increased mortality by its failure to reach statistical significance (p-value of 0.32). That this exact trend was demonstrated in their original study goes unmentioned.  In fact, the same magnitude of harm caused the authors of the CRASH trial to halt their study prematurely. Given the collective consistency with which this mortality detriment has been demonstrated across trials it should not be written off as fluctuations of random chance. Interpreting this literature in its totality, it becomes obvious that these recent examinations of steroids in head trauma are vastly underpowered to detect the true harms involved with the utilization of such an intervention.

In the discussion section of both their trials, the authors question why their patients fared better than those in the CRASH cohort. They hypothesize that the overall higher acuity of their patients may be responsible for this difference in outcomes. The authors recommend further studies be performed to elucidate this uncertainty. I would argue that their cohorts fared no better than the CRASH patients. In fact, the absolute increase in mortality was identical to that of the CRASH trial. It is only because these authors defined success with a disease oriented outcome of little clinical significance(HAP), that their cohorts appear to fare better than the far more robustly powered CRASH cohort. At this point it seems clear steroids in acute TBI are harmful. Further studies to clarify the magnitude of benefit of irrelevant outcomes seem unwarranted.

“Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial”
http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(14)70144-4/fulltext

The tPA Cochrane Review Takes Us For Fools

It’s been 5 years since the last Cochrane Review synthesizing the evidence regarding tPA in acute ischemic stroke.  Clearly, given such a time span, in an area of active clinical controversy, a great deal of new, important, randomized evidence has been generated!

Or, sadly, the only new evidence available to inform practice is IST-3 – a study failing to demonstrate benefit, despite its pro-tPA flaws and biases.  So, it ought not be a very exciting update, considering the 2009 version included 26 trials, and the 2014 update now includes only 27 trials.  Their summary conclusion, with only additional evidence of regression to the mean, ought remain essentially the same, or even less optimistic, right?

Of course not:

2009:
Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. This overall benefit was apparent despite an increase both in deaths (evident at seven to 10 days and at final follow up) and in symptomatic intracranial haemorrhages. Further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which thrombolysis may best be given in routine practice.

2014:
Thrombolytic therapy given up to six hours after stroke reduces the proportion of dead or dependent people. Those treated within the first three hours derive substantially more benefit than with later treatment. This overall benefit was apparent despite an increase in symptomatic intracranial haemorrhage, deaths at seven to 10 days, and deaths at final follow-up (except for trials testing rt-PA, which had no effect on death at final follow-up). Further trials are needed to identify the latest time window, whether people with mild stroke benefit from thrombolysis, to find ways of reducing symptomatic intracranial haemorrhage and deaths, and to identify the environment in which thrombolysis may best be given in routine practice. 

They added a neutral trial comprising 43% of the tPA subjects to the existing analysis, and now it can be decisively promoted “up to six hours”?  How is this conceivable?

So, in the most literal sense, technically, the authors’ statement is not untrue.  Analyses 1.12 and 1.13 aggregate all patients treated in trials between 0-6 hours, looking at mRS 0-2 and 0-1 at the end of follow up.  Indeed, for mRS 0-2, the OR favors thrombolysis at 1.17 (1.06 to 1.29), and for mRS 0-1, the OR favors thrombolysis at 1.29 (1.16 to 1.43).  Therefore, the authors are not falsely advertising tPA as beneficial for reducing death and dependency out to six hours – as long as you wear your pro-tPA blinders.

These authors, with multiple professional and financial conflicts-of-interest, simply choose to focus on inappropriate chunking of data for a theoretically time-dependent condition, rather than acknowledge their own analyses performed providing evidence to the contrary.  Analysis 1.21, in which they split out the patients treated into 0-3 and 3-6 hour cohorts, clearly demonstrates there is no basis upon which to claim benefit beyond 3 hours.  The OR for favorable outcome with thrombolysis in the 0-3 hour window is 1.53 (1.26 to 1.86), but the OR for 3-6 hours is 1.07 (0.96 to 1.20).  Then, the authors also neglect to mention Analysis 1.26, showing deaths are neutral between 0-3 hours, with an OR of 0.91 (0.73 to 1.13), but increased by thrombolysis in the 3-6 window, with an OR of 1.16 (1.00 to 1.35).

So, tPA after 3 hours: no functional outcome benefit and increased deaths – yet the authors are extolling the benefits of tPA to 6 hours?  There is no reasonable justification for such distorted reporting of their own analyses.  Simply unacceptable – and grossly misleading for the vast population of clinicians who do not or cannot access the full text, and only read the abstract.

Let’s be perfectly clear – I am not anti-tPA.  I am, however, opposed to the unfettered expansion of tPA as guideline-mandatory treatment to a larger eligible cohort – as is increasingly prevalent across contemporary literature, and fueled by manufactured-sponsored COI.  Acute ischemic stroke is a heterogenous disease, with varying underlying etiology and diverse cerebrovascular substrate.  It is clear there are subsets of patients for whom the likelihood of harm from tPA exceeds the benefit, and we ought to be using precision medicine to narrow the treatment population, not expand it.

Thanks to Rory Speigel (@EMNerd_) for alerting me to this publication.

“Thrombolysis for acute ischaemic stroke (Review)”
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000213.pub3/abstract

tPA: We Don’t Need No Stinkin’ Consent!

Yes, this the brave future imagined by pro-tPA colleagues:  there are neurologists in a van down by the river, and they’ll drive right to your house and give you tPA – without your consent!

This is a research letter from JAMA, in which researchers from UCSF performed a survey of patient preferences through an online cohort representative of the adult U.S. population over 50 years of age.  These authors, as they would lead you to believe, asked participants to compare their desire to receive CPR after cardiac arrest with their desire to receive tPA after a stroke.  75.9% of surveyed participants wanted CPR and 76.2% wanted tPA.  Therefore, these authors conclude:

“… there are equally strong empirical grounds for presuming individual consent to thrombolysis for stroke as for presuming individual consent to CPR.”

I am not an ethicist, so I’m unable to precisely articulate how odd this comparison is at face value.  Would any therapy patients would choose 75% of time mean we ought to presume consent?  Is CPR the “gold standard” for emergency consent?  There are interesting questions regarding how this data ought to be interpreted in the context of emergency consent I’m not qualified to answer.

However, I am qualified to comment on their methodology, i.e., the best way to get the answer you want: ask a question in such a way they’ll answer how you intend.  How did they ask patients if they wanted CPR?  They showed them a “depiction of probabilistic outcomes after paramedic-initiated CPR”.  This depiction is not provided in the text, only a reference to an article they used to make it.  For tPA?  They used a graphical depiction of the benefits of tPA from this article.  They do not specify which graphical depiction they used, but the final product of the previous pro-tPA physicians was this, Figure 3:

With a graphic like this, is it any wonder the patients surveyed were amenable to tPA?  Interestingly, the authors who created the graphical depiction state this graphic “complements the numeric text of a national patient education tool developed jointly by US neurology, emergency medicine, and stroke patient organizations.”  The link in their citations is broken, but I have found a reproduction here, which contains the following fantastic isolated quote:

“If given promptly, 1 in 3 patients who receive tPA resolve their symptoms or have major improvement in their stroke symptoms.”

It boggles the mind ACEP was complicit in approving this horrible flyer.  As you can now see, this seemingly trivial document has since catastrophically mutated into the terrifying basis of giving tPA without informed consent.

“Testing the Presumption of Consent to Emergency Treatment for Acute Ischemic Stroke”
http://jama.jamanetwork.com/article.aspx?articleid=1861784

There’s Been A Drive-By Lysing!

If you’ve been keeping up, a couple weeks ago JAMA had a theme issue for Neurology – which nowadays, apparently, is mostly tPA.  And, the latest and greatest – concierge Neurology!  In which they come to your house to give you lytics.

This is the Prehospital Acute Neurological Treatmentand Optimization of Medical care in Stroke Study (PHANTOM-S), conducted in Berlin, Germany, using the Stroke Emergency Mobile (STEMO) vehicle.  They compared time-to-thrombolysis during 46 weeks of standard care with 46 weeks of STEMO period – and, within STEMO period, operation of the vehicle was a week-on/week-off deployment.  Unsurprisingly, driving the tPA to the patient shaves 25 minutes off the alarm to tPA time.  Success!

MedPage Today, with it’s usual insightful analysis, breaks out a table of glowing secondary outcomes – improvements in in-hospital all-cause mortality, discharge to home, symptomatic intracranial hemorrhage, and overall tPA complications …

… before acknowledging all these improvements occurred even when the STEMO wasn’t deployed, and it was rather general stroke care improvements over the study period reflected in these secondary outcomes.  Additional praise is provided by James Grotta, who has started his own mobile stroke unit in Houston.  And, finally, Associated Editor Jeff Saver, of endless tPA conflict-of-interest disclosures, chimes in for the Editor’s audio summary.

I think it’s clear, between this and its preceding pilot study, that it is possible to drive a bus around with a stroke neurologist and a CT scanner and rule out intracranial hemorrhage.  The main concern might be over-treatment of stroke mimics, but these authors state the same number of patients treated in all observation windows ultimately received non-stroke diagnoses.  However, they report a baseline stroke mimic treatment rate of 2.2% – which is line with other literature describing institutions that don’t go looking very hard for non-stroke diagnoses after tPA.  Other institutions that require MRI signs of ischemic lesions have stroke mimic rates up to 15.5%, so I wouldn’t place much stock in this specific statistic as a measure of quality.

The last issue – a reasonable case can be made for safety as long as there’s a neurologist riding shotgun in the ambulance.  However, you’ll have to find neurologists willing to take such emergency call and support their salaries while they wait for deployment, which will end up being logistically and financially unworkable.  The next step, I presume, will be pre-hospital telestroke where paramedics are supervised by a remote neurologist.  A bright, or dim, future, depending on your view of tPA.

“Effect of the Use of Ambulance-Based Thrombolysis on Time to Thrombolysis in Acute Ischemic Stroke”
http://jama.jamanetwork.com/article.aspx?articleid=1861800