Category: Stroke

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

tPA ‘Em & Let ‘Em Bleed

NINDS was published in 1995.  We’ve been using tPA and other thrombolytics for myocardial infarction since well before that.  But, we still have no effective way to manage post-thrombolysis intracranial hemorrhage.

This retrospective registry review of 921 patients at the University of Texas identified 48 patients with symptomatic intracranial hemorrhage after tPA thrombolysis for acute stroke.  11 received FFP alone, 7 received FFP and cryoprecipitate, and 1 received cryoprecipitate.  Only two patients (4.6%) had mRS 0-2 after sICH, neither of whom received blood product administration.  There were baseline differences between groups, but overall mortality for any sICH was 41.8% – which may or may not be worse than mRS 4 or 5.

A 2010 review found similar futility in pro-coagulant administration, though in an even smaller case-series.  If the widespread proponents of tPA would like to subject ever-increasing numbers of patients to this complication, perhaps they ought to put as much energy into developing new treatments for hemorrhage as they do vilifying tPA skeptics?

“Clotting Factors to Treat Thrombolysis-related Symptomatic Intracranial Hemorrhage in Acute Ischemic Stroke.”
http://www.ncbi.nlm.nih.gov/pubmed/24321775

Post-script:  Thomas Deloughery writes in to note this has been recognized as a problem since at least 1989 … with zero progress since that time:
“Bleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management.”
http://www.ncbi.nlm.nih.gov/pubmed/2688504

Target: Stroke – “Success!”

The use of tPA has evolved rapidly over the last decade.  However, despite its increasing use, proponents have been dismayed to see eligible patients were still receiving tPA within 60 minutes of ED arrival only one-third of the time.  Thus, “Target: Stroke”, a set of key strategies to improve door-to-needle time introduced in 2010.

The initiative, described in this retrospective analysis of the Get With the Guidelines-Stroke registry, is very clearly successful.  Even taking into account the limitations in data quality, there is a clear inflection point in late 2010 or early 2011 at which participating hospitals began generally improving their door-to-needle time.  By mid-2013, over 50% of eligible patients were receiving their tPA within 60 minutes.

If the authors stop there, we have a respectable paper describing a successful quality intervention.

However, they also go one step further and try to link the door-to-needle improvements to outcomes.  They observe decreases in mortality, symptomatic intracranial hemorrhage, and tPA complications, and heavily associate these observations with faster tPA use – without seriously acknowledging any alternative explanation.

But, we know there have been many changes in stroke care over the last decade.  Stroke units, swallow evaluations, temperature management, and many other advances in post-stroke care have reduced mortality and complications.  However, the authors state:

“The in-hospital mortality benefit associated with the post-intervention vs preintervention periods for patients with acute ischemic stroke treated with tPA was of greater magnitude than the improvement observed for those not treated with tPA and for patients with hemorrhagic stroke cared for during the same time frame in these hospitals, suggesting this finding was the result of more than just general improvements in stroke care and outcomes.”

… but, despite claiming this – and having clearly done the analysis – they do not provide us with this data to inspect and compare.

They also dangerously assert:

“Although there have been concerns that attempting to achieve shorter door-to-needle times may lead to rushed assessments, inappropriate patient selection, dosing errors, and greater likelihood of complications, our findings suggest that more rapid reperfusion therapy in acute ischemic stroke is feasible … with actual reductions in complications.”

… when it has been clearly observed in multiple reviews of stroke mimics, the baseline rate of intracranial hemorrhage in patients without stroke is less than 1%.  Therefore, it is entirely consistent with the existing evidence that rushing to therapy – and treating mimics – will ultimately reduce overall intracranial hemorrhage.

Regardless, it’s the expected interpretation from a group of authors with a conflicts-of-interest statement so long it’s almost comedic:

Dr Fonarow reported serving as a member of the Get With The Guidelines (GWTG) steering committee; receiving significant research support from the National Institutes of Health; and being an employee of the University of California, which holds a patent on retriever devices for stroke. Dr Smith reported serving as a member of the GWTG steering subcommittee. Dr Saver reported serving as a member of the GWTG science subcommittee; the University of California, his employer, receives funding in exchange for his services as a scientific consultant for CoAxia, Grifols, Brainsgate, Lundbeck, Ev3, and Stryker regarding trial design and conduct; and the University of California holds a patent on retriever devices for stroke. Dr Reeves reported receiving salary support from the Michigan Stroke Registry and serving as a member of several American Heart Association (AHA) GWTG subcommittees. Dr Bhatt reported serving on advisory boards for Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; serving on the board of directors for Boston VA Research Institute and the Society of Cardiovascular Patient Care; serving as chair of the AHA GWTG steering committee; being a member of data and safety monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; receiving honoraria from the American College of Cardiology (editor, Clinical Trials, Cardiosource), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), WebMD (continuing medical education steering committees); serving as associate editor for Clinical Cardiology, section editor (pharmacology) for the Journal of the American College of Cardiology; receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, sanofi-aventis, The Medicines Company; and performing unfunded research for FlowCo, PLx Pharma, Takeda. Dr Hernandez reported receiving AHA pharmaceutical roundtable grant 0675060N and a research grant from Johnson & Johnson; and receiving honoraria from AstraZeneca and Amgen. Dr Peterson reported receiving research grants from Lilly, Johnson & Johnson, Bristol-Myers Squibb, sanofi-aventis, and Merck-Schering Plough partnership; and serving as principal investigator of the data analytic center for the AHA/American Stroke Association’s (ASA) GWTG. Dr Schwamm reported being the principal investigator of an investigator-initiated study of extended-window intravenous thrombolysis funded by the National Institute of Neurological Disorders and Stroke (clinicaltrials.gov/show/NCT01282242) for which Genentech provides alteplase free of charge to Massachusetts General Hospital as well as supplemental per-patient payments to participating sites; serving as chair of the AHA/ASA GWTG stroke clinical work group; serving as a stroke systems consultant to the Massachusetts Department of Public Health; and serving as a scientific consultant regarding trial design and conduct to Lundbeck (international steering committee, DIAS3, 4 trial) and Penumbra (data and safety monitoring committee, Separator 3D trial). Mr Zhao and Dr Xian reported not having any disclosures.
Target: Stroke is an initiative provided by the American Heart Association/ American Stroke Association (AHA/ASA). The GWTG-Stroke program also is provided by the AHA/ASA. The GWTG-Stroke program is currently supported in part by a charitable contribution from Janssen Pharmaceutical Companies of Johnson & Johnson. The GWTG-Stroke program has been funded in the past through support from Boeringher-Ingelheim, Merck, Bristol-Myers Squib/sanofi pharmaceutical partnership and the AHA pharmaceutical roundtable.

“Door-to-Needle Times for Tissue Plasminogen Activator Administration and Clinical Outcomes in Acute Ischemic Stroke Before and After a Quality Improvement Initiative”
http://jama.jamanetwork.com/article.aspx?articleid=1861802

Skull On, Skull Off, Disabled or Dead

What is a “good outcome” for stroke patients?  Is it “alive”?  Or is it “alive & independent”, as in most of the tPA trials?  Through what lens ought we interpret the findings of some of these highly intensive interventions for stroke?

This is DESTINY-II, which enrolled elderly patients with malignant intracranial swelling following significant MCA territory infarction.  In this study, patients were randomized either to usual care or hemicraniectomy, a potential life-saving intervention that relieves intracranial pressure and reduces cerebral herniation.  The untreated cohort had awful outcomes – at 12 months, zero patients were free from disability, zero had mild disability, and 5% had moderate disability.  The remainder were severely disabled in dead.  The hemicraniectomy cohort also had awful outcomes – at 12 months, zero patients were free from disability, zero had mild disability, and 6% had moderate disability.

So, of course, this study was stopped early because of overwhelming benefit to the hemicraniectomy cohort.

The key difference – hemicraniectomy patients survived to be severely disabled, while control patients died.  76% of patients in the control group died vs. 43% of the hemicraniectomy group.  Most of the difference was made up by patients with mRS 4: “Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance.“

Determining the value of survival with complete dependence vs. death is clearly a challenging ethical decision.  Should this therapy be more widespread, given the resource intensive care and the ultimately dismal disability outcomes?  Those questions remain to be answered – but at least this study helps us better share the prognosis of either option with patients and families.

“Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1311367

The Eloquence of Stroke Neurologists

Entertainingly enough, as tPA proponents continue their push for longer time windows and less-stringent inclusion criteria, Stroke recently published a sort of head-to-head debate regarding tPA within the 3 – 4.5h window.

Despite the breathless madness typically exhibited by stroke neurologists and the current Level B recommendations from the AHA, Lawrence Wechsler from the University of Pittsburgh writes a very reasonable critique of ECASS III, incorporating data from ATLANTIS and IST-3.  His general point, overall, is the theoretical effect size, if any, is small beyond 3 hours.  Therefore, he proposes patients should be carefully selected – perhaps by penumbral perfusion imaging.

His opponents, from Germany, in their response, offer a critique featuring this well-written, professional, academic segment:

Is advanced imaging necessary to make this decision? Why, No?! Would a lacunar versus nonlacunar syndrome make a difference here? No!! It would not make a difference within 3 hours, would it? And what about an MRI without perfusion imaging/diffusion weighted imaging mismatch or with proof of a lacunar stroke, would this make a difference? Hell, no!!! There is no evidence at all for this conclusion. And is there any reason to believe that rt-PA does not work in the 3- to 4.5-hour time window or that it does work only in “a carefully selected set of patients”? What the h…, No, No No!!!!

In keeping with Patrick Lyden’s lovely ad hominem attacks on Anand Swaminathan (“young”, “naive”), it is yet again abundantly clear some proponents of tPA have no response in reasonable, scientific debate other than nonsensical, authoritative bluster.

“The 4.5-Hour Time Window for Intravenous Thrombolysis With Intravenous Tissue-Type Plasminogen Activator Is Not Firmly Established”
http://www.ncbi.nlm.nih.gov/pubmed/24526061

“4.5-Hour Time Window for Intravenous Thrombolysis With Recombinant Tissue-Type Plasminogen Activator Is Established Firmly”
http://www.ncbi.nlm.nih.gov/pubmed/24526060

Again on Giving tPA to TIAs

When I suggested to Jeff Saver in JAMA his analysis of the Get With the Guidelines Registry may have become unbalanced due to the presence of TIAs within the tPA cohort, he went back to the NINDS data and identified seven patients from the placebo arm with TIAs.  Because 3 were in the 58 to 90 minute cohort and 4 were in the 91 to 180 minute cohort, he concludes there is an equal distribution of TIAs – and thus confounders – across all time periods.  This, of course, is nonsense – he is generalizing a handful of patients from the placebo arm from NINDS, a carefully controlled trial run by stroke neurologists, to the GTWG-Stroke registry, a cohort of community hospitals rushing to hit time-based stroke quality measures.  The contemporary evidence, such as this observational series from Japan, is that most TIAs present early in their symptom course – and earlier, if symptoms are more severe.

These authors retrospectively identified 464 patients admitted to 13 stroke centers in Japan with ultimate diagnosis of TIA based on complete clinical resolution of symptoms.  233 of them (55%) presented within the first three hours and the next 65 (15%) within six hours.  The common elements for the TIAs presenting earliest were the greatest severity of symptoms, primarily motor and speech disturbances.  A full 42% of their cohort had persistent symptoms upon arrival.

In the brave new world of tPA, hospitals are falling over themselves to treat these patients with thrombolytics – patients that ultimately would experience full clinical resolution of symptoms without intervention, and receive only the risks associated with tPA administration.  These patients ultimately make their way into the GWTG-Stroke registry, and come out the back end analysis looking like tPA miracles, “proving” time-to-treatment matters with tPA.  As “code stroke” protocols become more widespread, we will see even further such collateral damage.

“Factors Associated With Onset-to-Door Time in Patients With Transient Ischemic Attack Admitted to Stroke Centers”
http://www.ncbi.nlm.nih.gov/pubmed/24262324

Why Observational Data for tPA is Flawed

Much is made of retrospective comparisons derived from registry data in acute ischemic stroke.  The most egregious of these attempt to match a subgroup of tPA-treated folks with a control group not receiving tPA.

This publication, from an Austrian stroke registry, pulls 890 patients from 54,917 with mild (NIHSS <5) symptoms to perform a comparison matched on many clinical features.  In their matched comparison, 41% of tPA-treated patients were better off, 30% were identical on mRS, and 29% favored non-treatment.  Therefore, these authors declare there is an overall shift towards favorable outcome with tPA.

What is wrong with drawing anything but hypothesis-generating conclusions from this data (or, any retrospective, observational data)?  While the authors control for a few factors, there are many pre-existing comorbid conditions influencing treatment or non-treatment with tPA.  For example, a patient with advanced metastatic cancer will almost certainly be excluded from treatment with tPA – and certainly have poor 3-month functional outcomes – but that comorbid state cannot not be captured by this registry.  Then, just as we saw in IST-3, patients who are treated with tPA frequently receive more vigilant initial stroke care.  Adherence to clinical pathways as well as the control of hyperglycemia, fever, and swallowing dysfunction have profound effects on subsequent death and disability far exceeding the effect size supposed for tPA.  This registry, taking place over the course of a decade of evolving stroke care, cannot control for follow-up treatment and therapy.

This is, essentially, why all retrospective, observational comparisons are almost guaranteed to favor the tPA cohort.

Just as an added note – for anyone considering responding directly to the authors in the pages of Stroke – you will be charged $35 for typesetting for an electronic-only publication which then resides behind a paywall.  Traditional scientific journals are for profit, not for science – that’s where FOAMed comes in!

“Thrombolysis in Patients With Mild Stroke: Results From the Austrian Stroke Unit Registry”
http://stroke.ahajournals.org/content/early/2014/01/30/STROKEAHA.113.003827.abstract

My ACEP tPA Policy Critique

As some of you are aware, there is controversy regarding the use of tPA for acute ischemic stroke.  To this end, ACEP has opened up public comment for their recent relevant Clinical Policy Statement.

The comment form, however, is a bit of an odd and onerous format.  To spark discussion, to provide inspiration – and for public feedback/comment/correction – here are a few points from the initial draft of my response:
Page 225, Line 3, author list:
Area of Content / Concept – Conflict of Interest in Guideline Development Group (GDG)
The Institute of Medicine publishes recommendations regarding the composition and conflict of interest disclosures of a Clinical Practice Guideline (CPG) writing panel.  This tPA policy statement falls short on several accounts, most importantly:
Standard 2.1:  
The disclosures listed by the authors only narrowly address their direct financial relationships, but do not describe non-commercial, intellectual, and patient/public activities pertinent to the scope of the CPG.  For instance, authors do not fully describe their relationships with FERNE, a pharmaceutical-supported organization, nor other indirect and intellectual activities relevant to the CPG.
Standard 2.3:
The recommendation states members of the GDG should not participate in marketing activities or advisory board of entities whose interests are affected by the recommendations.  This standard does not appear to be met.
Standard 2.4:
Whenever possible, GDG members should not have COI.  If this is not possible, members with COIs should represent only a minority.  The chair, or co-chair, should not have COI.  This standard does not appear to have been met.
Standard 3.1:
The GDG should be multidisciplinary with methodological experts, clinicians, and patients.  The GDG members appear to be primarily clinicians and administrators, rather than patients and methodologic experts.
Standard 7:
The external review process is only briefly described, and the guideline was not open to public comment until this 60-day period.
Additional comments on the integrity of CPG come from a recent BMJ article, “Ensuring the integrity of clinical practice guidelines:  a tool for protecting patients.”  The recommendations from this publication are similar to the IOM recommendations, with the addition the GDG members ought to represent diverse viewpoints regarding the topic in question.  It does not appear this CPG represented any point of view other than a pro-tPA viewpoint.  The ACEP tPA clinical policy was evaluated using the “red flag” methodology by this article and found to be lacking.
Based on the COIs identified in this GDG, the output lacks face validity.
Page 227, Line 23:
Area of Content / Concept – Patient Management Recommendations
The guideline specifies offering IV tPA to acute ischemic stroke patients within 3 hours to be a Level A recommendation.  A Level A recommendation, according to the methodology of the CPG, states this indicates “Generally accepted principles for patient management that reflect a high degree of clinical certainty.”
The evidentiary table cites several articles as Class I evidence specifically relevant to the 3 hour timeframe (NINDS, ECASS II, and ATLANTIS B 0-3).  NINDS, by all accounts, shows benefit, while the effect size is debated by many based on the baseline characteristics of the treatment groups.  ECASS II is a negative trial; it is inappropriate to apply a subgroup analysis consisting of the 158 patients treated within 3 hours as the same level of Class I evidence.  The ATLANTIS B publication cited is also a very small subgroup analysis of a heavily modified trial stopped early for futility, and should not be considered the same level of Class I evidence.
Notably missing from this evidentiary table is ATLANTIS Part A – cited in the text, but apparently not considered as contributory to the CPG.  This is randomized, placebo-controlled evidence stopped early due to patient harms in the tPA cohort.  This merits inclusion in the evidentiary table as evidence of the harms of IV tPA.
The Lees meta-analysis, among others performed prior to 2010, is appropriately level II evidence.  However, it should be noted there are significant methodologic concerns associated with performing a meta-analysis that includes trials stopped early by their sponsors for futility or harms alongside trials allowed by their sponsors to run to their conclusion.  The evidentiary table notes “some of the analyzed studies were industry supported.”  To be more precise, all of the listed studies have substantial COI with industry – including employees of the sponsoring corporations listed among study authors – except NINDS, where the COI is minimized.
The remaining observational evidence is not relevant to a Level A recommendation.  The Hill and Wahlgren Phase IV studies are not placebo-controlled and only offer substantially limited, indirect, adjusted comparisons to a non-tPA treated population regarding safety and effectiveness.
My point, therefore, is NINDS is unique in support of tPA.  It is irresponsible to base a Level A treatment recommendation on a single positive study with a disputed effect size, whose results cannot be considered externally valid to current stroke practice.  NINDS – along with most evidence cited here – describes use in controlled trial environments of academic stroke centers supported by stroke neurologists.  There is insufficient evidence to support its general effectiveness, compared with standard treatment, in community Emergency Medicine.  Additionally, the observational evidence cited in the evidentiary table clearly describes a heterogenous acute stroke population, with varying levels of sICH risk, mortality risk, and capacity to benefit.  A CPG should not make a global recommendation for treating such a heterogenous disease without providing tools for physicians to communicate individualized risks and benefits.  Unfortunately, the placebo-controlled data are of insufficient quantity and quality to guide therapy.
A demonstration of the dangers of basing treatment decisions on small trials and small effect sizes is based in statistical theory.  Dr. Ioannidis demonstrates how “Most published research findings are false”, a hypothesis apparently borne out by “A decade of reversal:  an analysis of 146 contradicted medical practice.”
Furthermore, a Level A recommendation constitutes “generally accepted principles” with a “high degree of clinical certainty”.  If this were, indeed, the case, tPA for acute ischemic stroke would not be a controversial therapy 18 years past its introduction.  Respected U.S. Emergency Medicine experts in critical appraisal and knowledge translation, e.g., Jerome Hoffman, David Schriger, David Newman, Anand Swaminathan, and many others feel tPA for stroke remains an unproven and inadequately described therapy for acute ischemic stroke.  Indeed, Dr. Swaminathan ably debates Dr. Jagoda, one of the authors of this Clinical Policy in podcast, hosted by Scott Weingart.

Citation:  http://emcrit.org/podcasts/tpa-for-ischemic-stroke-debate/

Lest ACEP consider these objections simply a vocal minority or lunatic fringe, it should be noted active debate continues in the international literature as well.  Just last year, the BMJ posted a “Head to Head” debate regarding the proven efficacy of tPA in acute ischemic stroke.  An unscientific poll accompanying the article reported a slim majority of respondents did not feel tPA was proven effective.

Citation:  http://www.bmj.com/content/347/bmj.f5215

Additionally, there remains disagreement between international professional societies regarding the use of tPA in acute ischemic stroke.  While several countries endorse its use, others, such as Australia and New Zealand, remain concerned the strength of the evidence does not support widespread use.

Citations:
http://bit.ly/1nY6P18
http://bit.ly/1gRpYRs

In summary, the evidence does not support a Level A recommendation for tPA for ischemic stroke within 3 hours.

There is no reasonable justification for anything higher than a Level B recommendation – and even then, a caveat stating this has never been demonstrated as efficacious compared to usual therapy outside of controlled clinical trial environments.  Physicians may consider offering this therapy based on comfort, diagnostic certainty, supporting resources, and institutional commitment, but it should not be considered the standard of care.

Page 227, Line 28:
Area of Content / Concept – Patient Management Recommendations
The Level B recommendation given to IV tPA is inappropriate given the lack of unbiased evidence in support of treatment beyond the 3 hour time window.  This therapy is not approved in the U.S. and the Class I evidence regarding the 3-4.5 hour time window is conflicting.  ECASS, ECASS II, and ECASS III are manufacturer-sponsored studies of which only ECASS III demonstrated benefit.  ATLANTIS, also manufacturer-sponsored, enrolled patients similar to the NINDS criteria and showed harms beyond 5 hours, futility in the 3-5 hour window, and no usable insights in the 0-3 hour timeframe.  As Clark and Madden note, “Keep the three hour tPA window: the lost study of Atlantis” – ECASS III alone is not enough to refute prior evidence of either futility or harm.  There is a reason why the FDA still has not approved IV tPA beyond 3 hours.
ECASS III is also flawed regarding a baseline imbalance of prior stroke included in the placebo arm.  The absolute difference in percentage of patients with prior stroke is identical to the effect size offered by IV tPA.  Even more concerning regarding the internal validity of the findings, ECASS III offers this COI statement:
Supported by Boehringer Ingelheim.
Dr. Hacke reports receiving consulting, advisory board, and lecture fees from Paion, Forest Laboratories, Lundbeck, and Boehringer Ingelheim and grant support from Lundbeck; Dr. Brozman, receiving consulting and lecture fees from Sanofi- Aventis and consulting fees and grant support from Boehringer Ingelheim; Dr. Davalos, receiving consulting fees from Boeh- ringer Ingelheim, the Ferrer Group, Paion, and Lundbeck and lecture fees from Boehringer Ingelheim, Pfizer, Ferrer Group, Paion, and Bristol-Myers Squibb; Dr. Kaste, receiving consulting and lecture fees from Boehringer Ingelheim; Dr. Larrue, receiv- ing consulting fees from Pierre Fabre; Dr. Lees, receiving con- sulting fees from Boehringer Ingelheim, Paion, Forest, and Lund- beck, lecture fees from the Ferrer Group, and grant support from Boehringer Ingelheim; Dr. Schneider, receiving consulting fees from the Ferrer Group, D-Pharm, BrainsGate, and Stroke Treat- ment Academic Industry Round Table (STAIR) and lecture fees from Boehringer Ingelheim and Trommsdorff Arzneimittel; Dr. von Kummer, receiving consulting fees from Boehringer Ingel- heim and Paion and lecture fees from Boehringer Ingelheim and Bayer Schering Pharma; Dr. Wahlgren, receiving consulting fees from ThromboGenics, lecture fees from Ferrer and Boehringer Ingelheim, and grant support from Boehringer Ingelheim; Dr. Toni, receiving consulting fees from Boehringer Ingelheim and lecture fees from Boehringer Ingelheim, Sanofi-Aventis, and Novo Nordisk; and Drs. Bluhmki, Machnig, and Medeghri, being employees of Boehringer Ingelheim.
As I did not mention it previously, the meta-analysis by Lees also supplies this relevant COI statement:
KRL, RvK, DT, MK, and WH report honoraria from Boehringer Ingelheim for their roles in conduct of the ECASS trials. KRL reports honoraria from Lundbeck and Thrombogenics. DT reports honoraria from Novo-Nordisk, Pfizer, Sanofi-Aventis, and Boehringer Ingelheim. EB is an employee of Boehringer Ingelheim. RvK and JCG report being consultants to Lundbeck. GWA reports being a consultant to Lundbeck and Boehringer Ingelheim. SMD reports honoraria from Boehringer Ingelheim.
Confident translation in policy of clinical trial evidence having this level of COI is simply not reasonable.

Finally, it should also be noted the updated meta-analysis by Wardlaw accompanying the publication of IST-3 no longer shows a statistically significant benefit for alive and independent for the 3-6h time frame – moving from OR 1.17 (1.00 – 1.36) to OR 1.07 (0.96 – 1.20).  This ought to be viewed as regression to the mean as the sample size continues to increase.  Considering thrombolytic trials for myocardial infarction enrolled 140,000 patients, rather than the ~3500 tPA patients from the trials included in the Wardlaw meta-analysis, this should serve as a warning regarding the inadequacy of current evidence.

In summary, treatment beyond 3 hours can only be recommended based on “expert” (e.g., the sponsored mouthpieces of industry) opinion, should be considered only as part of prospective research, and absolutely not be recommended or implied to be standard of care.
Page 232, Line 28:
Area of Content / Concept – NINDS Exclusion Criteria
There is no mention of oral anticoagulation in these treatment recommendations, other than reference to the NINDS exclusion criteria regarding PTT and PT.
The safety of tPA given concomitant use of coumadin and the novel oral anticoagulants (direct thrombin inhibitors, factor Xa inhibitors) is not established.  Contradictory findings from meta-analyses and systematic reviews suggest increased risk of bleeding, even with INR <1.6.  Any CPG recommending offering IV tPA is remiss in excluding mention of these commonly prescribed medications in the population most at risk for stroke.
tPA cannot yet be considered safe when considered in the setting of anticoagulation, despite the NINDS inclusion criteria, in the absence of high-quality data on the subject.
Citations:

Maddening Lack of Perspective in Endovascular Stroke Therapy

Despite three negative trials in the New England Journal of Medicine last year, accompanied by an editorial calling for a moratorium on reimbursement for endovascular therapy for acute stroke, proponents of this therapy forge ahead.  The negative trials, at the very least, have encouraged researchers to recognize – where tPA advocates fail to see – that patient selection is key, and not all candidates eligible for endovascular therapy are likely to benefit.

However, these authors, despite their well-intentioned effort to better target endovascular interventions, completely miss the mark.  This is a retrospective review of patients undergoing endovascular therapy between 2008 and 2012, stratified by selection protocols.  In 2010, the institution switched from an “all-comers” strategy to an MRI diffusion-weighted imaging-guided protocol.  The hypothesis: patients selected for endovascular therapy on the basis MRI-guided infarct characteristics would display better outcomes than the “all-comers” selection cohort.

And, their registry provides them the necessary substrate.  Between 2008 and 2010, 85 patients with median NIHSS 17 underwent endovascular therapy with dismal outcomes:  9.5% mRS 0-2 at 30 days and 47.6% mortality.  After implementation of the imaging-based protocol, only half of eligible patients qualified – and of the 92 patients with median NIHSS 15.5 who eventually underwent endovascular therapy under the new protocol, 23.9% had mRS 0-2 and mortality dropped to 19.7%.  Victory!  So say these authors.

However, there’s another cohort visible only by its absence in their tabular data – the post-protocol group that did not undergo endovascular therapy.  These 87 patients, with a median NIHSS ~16.5, had imaging characteristics thought by these authors to not qualify for endovascular therapy.  For this group, 23.1% had mRS 0-2 and 30% mortality.  These outcomes are not statistically different from the endovascular group.

The authors do not in any manner address this inconsistency in their data set – and the seemingly favorable intervention of lack-of-intervention.  Rather than the authors’ conclusion imaging could guide therapy – the better conclusion is that endovascular therapy was frighteningly harmful to many in the pre-protocol phase, and simply reducing the number of patients undergoing unnecessary intervention improved global outcomes.  And, for just added perspective: the placebo group in NINDS, with median NIHSS 15, had 26% mRS 0-1 and 21% mortality at 3 months – and this is before the modern post-stroke care that does more to improve outcomes than tPA could ever claim.

The madness continues.

“Addition of Hyperacute MRI Aids in Patient Selection, Decreasing the Use of Endovascular Stroke Therapy”
http://stroke.ahajournals.org/content/early/2014/01/09/STROKEAHA.113.003880.short