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Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest – Part I

Thu, 19 Jul 2018 14:40:46 -0400 by
 
Also to be posted on ResearchBlogging.org when they relaunch the site.

The results are in from the only completed Adrenaline (Epinephrine in non-Commonwealth countries) vs. Placebo for Cardiac Arrest study.
 


 

Even I overestimated the possibility of benefit of epinephrine.

I had hoped that there would be some evidence to help identify patients who might benefit from epinephrine, but that is not the case.

PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) compared adrenaline (epinephrine) with placebo in a “randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest”.

More people survived for at least 30 days with epinephrine, which is entirely expected. There has not been any controversy about whether giving epinephrine produces pulses more often than not giving epinephrine. As with amiodarone (Nexterone and Pacerone), the question has been whether we are just filling the ICUs and nursing home beds with comatose patients.
 

There was no statistical evidence of a modification in treatment effect by such factors as the patient’s age, whether the cardiac arrest was witnessed, whether CPR was performed by a bystander, initial cardiac rhythm, or response time or time to trial-agent administration (Fig. S7 in the Supplementary Appendix). [1]

 

The secondary outcome is what everyone has been much more interested in – what are the neurological outcomes with adrenaline vs. without adrenaline?

The best outcome was no detectable neurological impairment.
 

the benefits of epinephrine that were identified in our trial are small, since they would result in 1 extra survivor for every 112 patients treated. This number is less than the minimal clinically important difference that has been defined in previous studies.29,30 Among the survivors, almost twice the number in the epinephrine group as in the placebo group had severe neurologic impairment.

Our work with patients and the public before starting the trial (as summarized in the Supplementary Appendix) identified survival with a favorable neurologic outcome to be a higher priority than survival alone. [1]

 


Click on the image to make it larger.
 

Are there some patients who will do better with epinephrine than without?

Maybe (I would have written probably, before these results), but we still do not know how to identify those patients.

Is titrating tiny amounts of epinephrine, to observe for response, reasonable? What response would we be looking for? Wat do we do if we observe that response? We have been using epinephrine for over half a century and we still don’t know when to use it, how much to use, or how to identify the patients who might benefit.

I will write more about these results later

We now have evidence that, as with amiodarone, we should only be using epinephrine as part of well controlled trials.

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Also see –

How Bad is Epinephrine (Adrenaline) for Cardiac Arrest, According to the PARAMEDIC2 Study?

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Footnotes:

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[1] A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.
Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R; PARAMEDIC2 Collaborators.
N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMoa1806842. [Epub ahead of print]
PMID: 30021076

Free Full Text from NEJM

All supplementary material is also available at the end of the article at the NEJM site in PDF format –

Protocol

Supplementary Appendix

Disclosure Forms

There is also an editorial, which I have not yet read, by Clifton W. Callaway, M.D., Ph.D., and Michael W. Donnino, M.D. –

Testing Epinephrine for Out-of-Hospital Cardiac Arrest.
Callaway CW, Donnino MW.
N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMe1808255. [Epub ahead of print] No abstract available.
PMID: 30021078

Free Full Text from NEJM

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Filed Under: 2018 ACLS Guidelines, ACLS, Common Sense, Critical Judgment, Drug Shortages, Epinephrine, Ethics, Evidence, Heresy, Intubation, Lasix, Mythology, Narrative Fallacy, Oxygen, Pharmacology, Placebo, Potentially Reversible Causes, Probability, Research, Research Blogging, Resuscitation Theater, tPA

Alternative Medicine, Wishful Thinking, and Irresponsible Drug Pushers

Thu, 13 Feb 2014 13:00:13 -0500 by
 

Most emergency physicians avoid using homeopathy, acupuncture, Reiki, and other alternative medicine because there is no valid evidence that these treatments work, or because of they are not considered standards of care, or because there is no recommendation to give them from ACEP (American College of Emergency Medicine).

This is good, because alternative medicine is fraud.

Is there an alternative field of aerodynamics making planes for us to fly? Where is this alternative science?

Are people using alternative electricity to power their homes? Where is this alternative science?

According to the homeopathy hypothesis, the more dilute something is, the more powerful it is. We could solve the world’s energy problems – if the alternative science of homeopathy were anything more than wishful thinking.
 

How does that relate to emergency medicine?

When it comes to emergency treatments for cardiac arrest, stroke, heart failure, possible spinal cord injury, et cetera, many emergency physicians are just as superstitious as your local witch doctor. Currently, the most prominent example of alternative emergency medicine is tPA (Alteplase) for acute ischemic stroke.
 

But tPA, approved for strokes in 1996, only works if given within 4.5 hours of a stroke.[1]

 

That is an optimistic interpretation of the research –
 

The recent release of the American College of Emergency Physicians guideline recommending the use of tPA for ischemic stroke is remarkable. While it is unsurprising that a professional guideline flouts science, the publication is striking for its casual tone and its methodologically inexplicable review of evidence. Scientific thinking is absent.[2]

 

The evidence is horribly flawed, but the advocates respond just as we expect alternative medicine pushers to respond – with logical fallacies.

Ad hominem attacks on those who criticize the bad research.
 

These few persistent myths about thrombolytic therapy were first promulgated by self-appointed ‘expert critics’ who are unabashedly anti-intellectual in their opposition to this therapy. They decline to either read or attempt to understand data and rigorous analysis of that data.[3]


Alternative medicine pusher Dr. Patrick Lyden.
 

What is the appropriate time period for giving tPA?
 


IST-3 time to treatment randomization and outcomes detail with my edits for clarity.[4]
 

Patients get better if tPA is begun within 3 hours, get worse if tPA is begun between 3 hours and 4 1/2 hours, but get better when tPA is begun after more than 4 1/2 hours.

Clearly, there is some strong evil magic that is working against tPA in that 3 to 4 1/2 hour time period, but it is all unicorns and rainbows the rest of the time.

Does that make sense?

No.

That suggests that the evidence we have does not adequately assess the effects of tPA for acute ischemic stroke.

Reasonable people can disagree, but Dr. Lyden appears to be calling those who disagree biased just because they disagree. This is bad science and bad medicine.

We need research that is well controlled, not research that requires a lot of excuses.
 

MedPage Today is providing a good forum for discussion of this actual medical controversy and not just promoting the ad hominem criticisms of Dr. Lyden. There are links to plenty of other sites discuissing the problems with the evidence.[5]

I most recently wrote about this here – The Debate on tPA for Ischemic Stroke at EMCrit – What Does the Research Really Say?

I am not an emergency physician, so this is not something that affects my care of patients. I do not have to worry about being sued for not giving tPA and being accused of allowing a bad outcome. I do not have to worry about being sued for giving tPA and being accused of producing a bad outcome.

If you are an ACEP member, tell ACEP what you think of the evidence, or the flaws in the evidence.

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Footnotes:

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[1] Few stroke patients get clot-busting drug
Liz Szabo,
USA TODAY
10 a.m. EST February 13, 2014
Article

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[2] The Guideline, The Science, and The Gap
Wednesday, April 17, 2013
Dr. David Newman browngorilla540
Smart EM
Article

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[3] ER Briefs: tPA ‘Works’, ACEP on Target
Published: Feb 10, 2014
By Elbert Chu
Interview with Patrick D. Lyden, MD
Article

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[4] The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.
IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, Arauz A.
Lancet. 2012 Jun 23;379(9834):2352-63. doi: 10.1016/S0140-6736(12)60768-5. Epub 2012 May 23. Erratum in: Lancet. 2012 Aug 25;380(9843):730.
PMID: 22632908 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

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[5] ER Briefs: Open Season on ACEP tPA Guidelines
Published: Jan 29, 2014 | Updated: Jan 30, 2014
By Elbert Chu
Article
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Filed Under: 'Alternative' Medicine, Ethics, Evidence, Heresy, Science, tPA

The Debate on tPA for Ischemic Stroke at EMCrit – What Does the Research Really Say?

Fri, 31 Jan 2014 14:00:02 -0500 by

It puts the tPA in the patient, or else it gets the hose, again!

Should we look only at the so-called positive studies?

The proponents of tPA (Alteplase) are not trying to defend the other studies. They have a hard enough time putting a positive spin on the studies they want us to look at – just not too closely.[1]

Dr. Scott Weingart decided to bring two doctors together to discuss the problems with the research and whether those problems can be rationalized away (Not his description). I do not have the possibility of giving, or withholding tPA, so I do not have to worry about being punished for violating clinical policies – at least not when it comes to tPA. 😉
 

The debate seemed relevant because ACEP, a major US emergency medicine organization, released clinical guidelines markedly increasing stress on thrombolysing stroke. These clinical guidelines were sent back by ACEP’s council for further commentary and assessment, a move unprecedented in the history of the organization.[2]

 

Dr. Andy Jagoda presents the pro argument.

The research is not really that bad, just don’t suggest that the studies should be repeated with proper research methodology, because it would be improper to withhold the standard of care.

Organizations have looked at the research and made this a recommendation, so you have to justify not giving tPA, or you face punishment.
 


 

Bad standards of care are still bad medicine.
 

A decision not to use Alteplase in the appropriate setting is acceptable but clinical decision making must be well supported in the medical record[2]

 

Allow me to put that in perspective.
 

A decision not to use Alteplase in the appropriate setting is acceptable expected but clinical decision making must be well supported is taken for granted in the medical record.
 

Should any treatment be given without justification?

This is probably the biggest problem with medicine.

All treatment should require justification, every time.

Should treatment be justified with flawed research?

Dr. Anand Swaminathan gave the con argument.
 


 

The research is flawed.

The failure of the recommending organizations to identify these flaws does not mean that the flaws do not exist or that the flaws are insignificant.
 


IST-3 time to treatment randomization and outcomes.[3]
 

What is the magic that causes a good outcome when tPA is given at 0-3 hours, a reversal to a bad outcome at 3-4 1/2 hours, and another reversal back to a good outcome at over 4 1/2 hours?

The longer we wait, the more effective it is?

Isn’t this just a variation on the nonsense of homeopathy? The less we give, the greater the effect.

Here is the detail of the effect of time on outcomes, when giving tPA.
 


IST-3 time to treatment randomization and outcomes detail with my edits for clarity.[3]
 

Magic™
 

A decision not to use Alteplase Magic™ in the appropriate setting is acceptable but clinical decision making must be well supported in the medical record.
 

Go watch/listen to the debate.
 

Also view the pro and con slides and read the detailed review of tPA for acute ischemic stroke at EM Lyceum[4] and Dr. David Newman’s much shorter review of the guideline problems at Smart EM.[5]

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Footnotes:

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[1] The raw data of the NINDS trial should be made public
Dr. Jeffrey Mann
BMJ
Rapid response letter

Unfortunately, it has been years since Dr. Mann discontinued his EM Guidemaps site, where he posted the raw data that the NINDS investigators finally sent him in 2003 (8 years after the study was published), and I no longer have a copy of what he posted.

Researchers should not keep their data secret.

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[2] Podcast 116 – the tPA for Ischemic Stroke Debate
EMCrit
January 28, 2014
Dr. Andy Jagoda (pro) vs. Dr. Anand Swaminathan (con).
Podcast/Videocast page with links to the slides used by both doctors.

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[3] The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.
IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, Arauz A.
Lancet. 2012 Jun 23;379(9834):2352-63. doi: 10.1016/S0140-6736(12)60768-5. Epub 2012 May 23. Erratum in: Lancet. 2012 Aug 25;380(9843):730.
PMID: 22632908 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

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[4] tPA in ischemic stroke, “answers”
Posted on August 30, 2013
EM Lyceum
Article

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[5] The Guideline, The Science, and The Gap
Wednesday, April 17, 2013
Dr. David Newman browngorilla540
Smart EM
Article

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Filed Under: Critical Judgment, EMCrit, Evidence, Heresy, Research, tPA

Does the Goal of a Pulse Lead to Bad Resuscitation Decisions

Tue, 26 Mar 2013 10:30:47 -0400 by
ResearchBlogging.org
 

First, this is a paper that was just added to the Articles In Press for Resuscitation with the editing not yet completed. Do not fault the authors for the lack of polish. The paper does address some interesting aspects of resuscitation.

ROSC (Return Of Spontaneous Circulation) is the goal for many people.

ROSC is a red herring.

Those of us who think ROSC is important do not seem to understand how much long-term damage we can do in our attempts to get ROSC, or to get ROSC quickly.

This study helps to point out some of the inconsistencies with our ROSC fetish.

Here is a table of the results from the study comparing early epinephrine (≤10 minutes) with late epinephrine (>10 minutes).
 


Click on images to make them larger.
 

Everything highlighted in blue is favoring early epinephrine and statistically significant.

Overall, things look good for early epinephrine, but VF/VT (Ventricular Fibrillation/Ventricular Tachycardia) is most responsive to resuscitation, yet the results for VF/VT never reach statistical significance. VF/VT may also be most associated with an early response

There is only a trend toward better ROSC for VF/VT, but as with the NINDS study of tPA for ischemic stroke, the healthiest patients are in the intervention group, so they are expected to have better outcomes.
 
With asystole there are survivors with late epinephrine, but no survivors with early epinephrine. What should we make of that? It is far from statistically significant, but there is not even a trend toward more ROSC with early epinephrine.
 

PEA (Pulseless Electrical Activity) has not just a trend toward more ROSC with early epinephrine, the results are statistically significant.

One of the reasons may be that PEA is sometimes due to assessment problems. We used to call it EMD (Electro-Mechanical Dissociation) because many of us assumed that if no pulse could be palpated, there was no cardiac output. These were termed pseudo-EMD, since imaging could show that there is heart motion, even though there is no palpable pulse.

I have had a handful of patients who were awake and alert, but did not have any palpable pulses. Clearly, EMD is not a description of reality.

How many of these patients are responding to being shaken up, rather than to the mechanical effects of chest compressions in the circulation? We do not know.
 

Early Epi may increase blood pressure to allow palpation of a pulse in cases with presumed PEA, but who are actually cases of “pseudo-PEA” which have some cardiac output but not enough to be identified clinically.[1]

 
 

Modified portion of EMS 12 Lead image.
 

Then there are the expected confounders in this kind of study. Faster response times would be expected to result in earlier epinephrine and less deterioration of the rhythm to asystole.
 


 

The faster response times occur in fewer patients, so there should be a much wider confidence interval/standard deviation. That is not the case, because there is an upper limit on the numbers that can be included. The numbers include response time, time to patient contact, time to establish access, and time to epinephrine. All of those have to be less that 11 minutes combined.

Bystander CPR is much more common with early epinephrine. This may be related the higher incidence of arrest in public, but the bystander CPR rate is about twice as high as the rate of arrest in public.
 


 

With early epinephrine we have a decrease from the odds of ROSC to the odds of survival.

With witnessed arrest, bystander CPR, and VF/VT the opposite is true.

With VF/VT the difference is dramatic.

Is this an indication of the effect of epinephrine on survival that we have seen in other studies?
 


 

 

Clearly more work is needed to understand the importance of the timing of epi administration and its impact on outcomes from OHCA.[1]

 
OHCA is Out of Hospital Cardiac Arrest.

Clearly more work is needed to understand the importance of the timing effects of epi administration and its impact on outcomes from OHCA.

Why should we assume that it is the timing and not the drug?

Maybe the problem is using such a drug that is so dangerous to the heart to treat heart problems.

Samuel Hahnemann would love this use of epinephrine, just at a much lower dose.

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Footnotes:

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[1] Rapid Epinephrine Administration Improves Early Outcomes in Out-of-Hospital Cardiac Arrest.
Koscik C, Pinawin A, McGovern H, Allen D, Media D, Ferguson T, Hopkins W, Sawyer K, Boura J, Swor R.
Resuscitation. 2013 Mar 21. doi:pii: S0300-9572(13)00175-5. 10.1016/j.resuscitation.2013.03.023. [Epub ahead of print]
PMID: 23523823 [PubMed – as supplied by publisher]

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Koscik, C., Pinawin, A., McGovern, H., Allen, D., Media, D., Ferguson, T., Hopkins, W., Sawyer, K., Boura, J., & Swor, R. (2013). Rapid Epinephrine Administration Improves Early Outcomes in Out-of-Hospital Cardiac Arrest Resuscitation DOI: 10.1016/j.resuscitation.2013.03.023

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Filed Under: ACLS, Epinephrine, Heresy, Research Blogging, tPA

Methodology of tPA Studies – Comment from Joshua

Wed, 30 Jan 2013 08:00:00 -0500 by
 

In response to my criticism of the ACEP (American College of Emergency Physicians) polict statement on Genentech’s r-tPA (recombinant tissue Plasminogen Activator) – alteplase (Activase®),[1] Joshua responded with these comments on what I cited/quoted. I think this is a first for me. –
 

First of all, IST-3 is a very large trial, involving more than 3000 subjects. Nortin Hadler, in his book Rethinking Aging, wisely suggests that whenever a very large trial is required to show statistical benefit, it means that the purported benefit cannot be clinically important.19 [2]

I disagree. When we are unable isolate a single variable (in this case administration of tPA) a large scale study may be the only way to identify outcomes attributable to the intervention (good or bad). The further from treatment to identifiable outcome and the more variables that can’t be (or simply are not) accounted for the larger the sample size should be.

 

There are several reasons I did not use that quote. I would have used an earlier book[3] as the source of that idea.

You do raise an important point. If few variables have been controlled for, are we measuring what we think we are measuring?

You appear to be making one of the same arguments that Dr. Lyden made. That enough data makes the flawed methods irrelevant.

I do not agree with that.

Dr. Lyden wrote –
 

The study leadership invoke a concept known as “large simple” trials, meaning trials that seek power by simplifying protocols and reducing data collection to a bare minimum in hopes of enhanced recruitment. Large simple trials may be an answer to the continuing difficulty getting clinical trials finished on budget and in time.[4]

 

And –
 

When reorganized, the trial became an unblinded trial with a design that sounds rigorous: “prospective, randomized, open, blinded end point” (PROBE). The investigators have written that their end point is blinded because a centralized researcher, unaware of the patient’s treatment group, contacts the patient or family member 6 months after stroke and attempts to derive a modified Rankin Scale from a questionnaire or telephone call.[4]

 

While this does make things more simple, it does not appear to be capable of producing blinded data, but it may blind some people to the fatal flaws of the study methods.
 

If we have only one variable that is the same among thousands of patients, then we might draw some conclusions, but only tentatively. There could easily be other variables which are not universally present and are not being controlled for, yet may have much greater influence on the outcomes. We would not know what is being measured.

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There’s a lot more that goes into the treatment of stroke patient than just whether or not they received fibrinolytic therapy. How many patients received rehabilitative care? How many were treated for hypertension and if so with what? How was patient weight calculated with an administration dose that’s weight dependent? If you only have 100 patients 1 or 2 nurses screwing up their drug calculations (of course that never happens and it ALWAYS gets reported ;-)) is a difference of 1-2% when evaluating final outcomes. What about 10 patients receiving anti hypertensive therapy in a sample size of 100? If 8 out of those ten patients have a negative outcome what’s to say that the combination of therapies and not TPA itself is responsible for this 8% increase in patients with increased neurological deficit at the 90 day mark? The larger the sample size the more you can negate the weight of these variables. While it’s not unreasonable to assume that 1 or 2 nurses may inadvertently administer an incorrect dose assuming that 100-200 nurses in a sample size of 1000 would do the same would suggest that tPA is the last thing we should be worried about when evaluating our patient’s outcomes.

 

The variability in competence and variability in methods are some of the problems that become more difficult to address in larger studies, but they may reflect the diversity in treatment that exists across the country, or around the world.
 

The substantial increased rate of symptomatic intracerebral hemorrhage among tPA-treated patients has tempered enthusiasm for the rapid adoption of tPA as routine care, in part because of the concern that treatment may be less safe in routine clinical practice than in the highly monitored setting of a clinical trial.[5]

 

This raises a serious problem.

In theory, there is no difference between theory and practice. But in practice, there is.
― Yogi Berra

If tPA works tolerably only during studies, but does a lot damage in use outside of controlled studies, is tPA too dangerous to use outside of controlled trials?

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Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.

If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.[3] [6]

Why are we suprised that pharmacuetical manufacturers are helping write our clinical guidelines?
(http://www.manhattan-institute.org/html/fda_05.htm)(http://www.sciencebasedmedicine.org/index.php/what-does-a-new-drug-cost/ <– read both parts)

It takes a lot of money to conduct phase 2 and 3 drug trials, though as the second article points out the actual cost is probably significantly skewed intentionally. But even at a conservate estimate of $43.4 million that's a lot of money to be gambling. So it's no wonder that they want the best chance at a possible outcome and hire people to make it happen.

 

Genentech should not have any control over who writes policy statements.

It is not a surprise that a drug company would attempt to influence policy statements, but it should not be so easy for any drug company to succeed.
 

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More so than full financial disclosure (because given the cost there's only one entity that can afford it so it's usually safe to assume who's paying to make it happen) I'd like to see a better explanation of how patients are treated in their entirety. Give me ALL the data and not just what you want me to see or what magical mathematical formula you think justifies what you've written in your abstract and let me be the one to interpret it. It's kind of like EPI in cardiac arrest. We may find that the drug is not beneficial for everyone but should instead be reserved for a particular subset of patients.

 

The quality of the research that is published does leave a lot to be desired. How much would it cost to add an on-line data file supplement, or several file supplements, of the raw data to the paper?

Not much.

How much do some of the researchers want to hide this information?

Probably very much.

Along with requiring registering the study with ClinicalTrials.gov, this is something that should be simple to achieve high compliance on. The reality is only about half of trials were registered prior to enrolling patients.[7] Improvements in research quality take time, even though they seem as if they should be no-brainers.

One of the big problems with NINDS was the refusal of the NINDS investigators to release the raw data.[8],[9]

The biggest problem may be the expectation that we will successfully develop drugs in laboratories, when this is not the way we have historically come up with useful drugs.

We would like a drug better than warfarin (Coumadin), but the designer drugs do not seem to be better. The designer anti-clotting drugs only seem to improve surrogate endpoints over warfarin, but we spend a lot on them and that may increase dramatically.

A lot of patients studied, but no important difference in outcomes. Sometimes, when a very large trial is required to show statistical benefit, it means that the purported benefit cannot be is not clinically important.
 

Image credit.

Where is Waldo?

Is Waldo’s location clinically significant?

Click on the image to make the image larger, but making it larger won’t make Waldo any more clinically significant. 😉

There he is.
 

Image credit.
 

“Spinal immobilization” is one area where the results will require huge numbers, the number of affected patients will be tiny, but the importance of the outcomes will be very important clinically.

The sad thing is that so many people do not want to know how much harm we may be causing or if we could improve care.

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Footnotes:

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[1] Can we trust drug companies to provide accurate information about their products? Part II
Mon, 28 Jan 2013
Rogue Medic
Article

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[2] How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3).
Hoffman JR, Cooper RJ.
Emerg Med Australas. 2012 Oct;24(5):473-6. doi: 10.1111/j.1742-6723.2012.01604.x. No abstract available.
PMID: 23039286 [PubMed – in process]

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[3] Fiction And Fantasy In Medical Research: The large scale randomised trial
By James Penston
Published by London Press, 2003
ISBN 0954463617, 9780954463618
144 pages
GoogleBooks link

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[4] In anticipation of International Stroke Trial-3 (IST-3).
Lyden PD.
Stroke. 2012 Jun;43(6):1691-4. Epub 2012 May 3. No abstract available.
PMID: 22556196 [PubMed – indexed for MEDLINE]

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[5] Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department.
This clinical policy is the result of a collaborative project of the American College of Emergency Physicians and the American Academy of Neurology.
Ann Emerg Med. 2013 Feb;61(2):225-43. doi: 10.1016/j.annemergmed.2012.11.005. No abstract available.
PMID: 23331647 [PubMed – in process]

Free Full Text Download in PDF format from Elsevier.

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[6] New ACEP tPA Clinical Policy
Wednesday, January 23, 2013
EM Literature of Note
Article

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[7] Characteristics of clinical trials registered in ClinicalTrials.gov, 2007-2010.
Califf RM, Zarin DA, Kramer JM, Sherman RE, Aberle LH, Tasneem A.
JAMA. 2012 May 2;307(17):1838-47. doi: 10.1001/jama.2012.3424.
PMID: 22550198 [PubMed – indexed for MEDLINE]

Free Full Text from JAMA.

The proportion of trials registered before beginning participant enrollment increased over the 2 time periods: from 33% (9041/27 667) in October 2004–September 2007 to 48% (19 347/40 333) in October 2007–September 2010.

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[8] Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
[No authors listed]
N Engl J Med. 1995 Dec 14;333(24):1581-7.
PMID: 7477192 [PubMed – indexed for MEDLINE]

Free Full Text from New England Journal of Medicine.

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[9] The raw data of the NINDS trial should be made public
Dr. Jeffrey Mann
BMJ
Rapid response letter

Unfortunately, it has been years since Dr. Mann discontinued his EM Guidemaps site, where he posted the raw data that the NINDS investigators finally sent him in 2003, and I no longer have a copy of what he posted.

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Filed Under: Ethics, FDA, Heresy, Pharmacology, Research, tPA

Can we trust drug companies to provide accurate information about their products? Part II

Mon, 28 Jan 2013 08:00:23 -0500 by
 

I am continuing to look at the problems with drug companies promoting drugs for uses that have not been approved by the FDA (Food and Drug Administration.The Second Circuit Court panel’s ruling allows drug company representatives to discuss/promote off-label use of their drugs.[1] A friend sent an email including the following –
 

This has nothing to do with the discussion of off-label uses in other forums. It has to to with making sure that drug representatives, with huge financial interest in the sale of their drug, both personal and institutional, cannot just make $#!+ up to sell their drug.

 

Unfortunately, the drug companies can just make $#!+ up to sell their drug. Even with drugs used as approved by the FDA.

Look at Genentech’s r-tPA (recombinant tissue Plasminogen Activator) – alteplase (Activase®).
 

Note: Within any time window, once the decision is made to administer IV tPA, the patient should be treated as rapidly as possible. As of this writing, tPA for acute ischemic stroke in the 3- to 4.5-hour window is not FDA approved.[2]

 

Who needs to get their drug reps to encourage the off-label use of a drug, when they can get doctors funded by drug companies to write practice guidelines that recommend off-label use?
 

Does the research support aggressive use for suspected acute ischemic stroke?

A. Within 90 minutes of symptom onset.

B. Within 180 minutes of symptom onset.

C. Within 270 minutes of symptom onset.

D. Within 360 minutes of symptom onset.

E. As long as we massage the data, we can give a fibrinolytic to whomever we want whenever we want.
 

Image credit.
 

ACEP (American College of Emergency Physicians) just had a policy statement on tPA for acute ischemic stroke written by a bunch of doctors who receive money from the drug companies affected by policy statement.

How much attention was paid to the criticism of the fatal flaws of some of these studies?

Little to none, based on the citations.

Only one paper by Dr. Jerome Hoffman is cited. Nothing by Dr. Jeff Mann is cited.

Dr. Mann’s papers –
 

Truths about the NINDS study: setting the record straight.
Mann J.
West J Med. 2002 May;176(3):192-4. No abstract available.
PMID: 12016245 [PubMed – indexed for MEDLINE]
 

tPA for acute stroke: balancing baseline imbalances.
Mann J.
CMAJ. 2002 Jun 25;166(13):1651-2; author reply 1652-3. No abstract available.
PMID: 12126317 [PubMed – indexed for MEDLINE]
 

NINDS Reanalysis Committee’s reanalysis of the NINDS trial.
Mann J.
Stroke. 2005 Feb;36(2):230-1; author reply 230-1. Epub 2005 Jan 6. No abstract available.
PMID: 15637327 [PubMed – indexed for MEDLINE]
 

Sex-based differences in response to recombinant tissue plasminogen activator in acute ischemic stroke.
Mann J.
Stroke. 2005 May;36(5):929; author reply 929. No abstract available.
PMID: 15867164 [PubMed – indexed for MEDLINE]
 

Emergency physician survey: recombinant tissue plasminogen activator for stroke.
Mann J.
Ann Emerg Med. 2006 Oct;48(4):476; author reply 477. No abstract available.
PMID: 16997689 [PubMed – indexed for MEDLINE]
 
 

Dr. Hoffman’s papers –
 

Predicted impact of intravenous thrombolysis. Another trial is needed.
Hoffman JR.
BMJ. 2000 Apr 8;320(7240):1007. No abstract available.
PMID: 10809554 [PubMed – indexed for MEDLINE]
 

Should physicians give tPA to patients with acute ischemic stroke? Against: and just what is the emperor of stroke wearing?
Hoffman JR.
West J Med. 2000 Sep;173(3):149-50. No abstract available.
PMID: 10986160 [PubMed – indexed for MEDLINE]
 

Thrombolytic therapy for acute ischemic stroke – Tissue plasminogen activator for acute ischemic stroke: Is the CAEP Position Statement too negative?
Hoffman JR.
CJEM. 2001 Jul;3(3):183-5. No abstract available.
PMID: 17610781 [PubMed]
 

Annals supplement on the American Heart Association proceedings.
Hoffman JR.
Ann Emerg Med. 2001 Nov;38(5):605. No abstract available.
PMID: 11679880 [PubMed – indexed for MEDLINE]
 

Alteplase for stroke. Why were these authors of the commentaries chosen?
Hoffman JR.
BMJ. 2002 Jun 29;324(7353):1581; author reply 1581. No abstract available.
PMID: 12092608 [PubMed – indexed for MEDLINE]
 

Tissue plasminogen activator (tPA) for acute ischaemic stroke: why so much has been made of so little.
Hoffman JR.
Med J Aust. 2003 Oct 6;179(7):333-4. No abstract available.
PMID: 14503891 [PubMed – indexed for MEDLINE]
 

Stroke thrombolysis: we need new data, not more reviews.
Hoffman JR, Cooper RJ.
Lancet Neurol. 2005 Apr;4(4):204-5. No abstract available.
PMID: 15778096 [PubMed – indexed for MEDLINE]
 

Thrombolysis for stroke: policy should be based on science, and not on politics, money or fear of malpractice.
Hoffman JR.
Emerg Med Australas. 2006 Jun;18(3):215-8. No abstract available.
PMID: 16712529 [PubMed – indexed for MEDLINE]
 

A graphic reanalysis of the NINDS Trial.
Hoffman JR, Schriger DL.
Ann Emerg Med. 2009 Sep;54(3):329-36, 336.e1-35. doi: 10.1016/j.annemergmed.2009.03.019. Epub 2009 May 23.
PMID: 19464756 [PubMed – indexed for MEDLINE]

RESULTS:
Final outcomes were highly dependent on stroke severity. In many graphs, the small difference between groups favored tissue plasminogen activator, particularly when baseline NIHSS score was between roughly 5 and 22. These differences diminish or disappear when 90-day change in NIHSS is graphed. Our graphs fail to support the time-is-brain hypothesis.

^ This is the only paper by Dr. Hoffman that is cited.
 

How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3).
Hoffman JR, Cooper RJ.
Emerg Med Australas. 2012 Oct;24(5):473-6. doi: 10.1111/j.1742-6723.2012.01604.x. No abstract available.
PMID: 23039286 [PubMed – in process]

The author of this commentary – and by extension the editors of Stroke who approved it – ultimately concludes that despite its many flaws, there is much to learn from IST-3.2 We agree . . . although given that the actual results of IST-3 uniformly failed to show benefit, even in the face of severe bias, we believe the lessons are precisely the opposite of those being trumpeted by the study’s own authors.1

 

the actual results of IST-3 uniformly failed to show benefit, even in the face of severe bias,

That is the problem. Bias.

When examining treatments where people can honestly come to opposite conclusions about the efficacy of a treatment, we do need to consider the effect of bias on the part of those who strongly endorse treatments based on such ambiguous evidence.

Is it also possible that there is bias on the part of those critical of the treatment? Absolutely, but . . .
 

Our bias should be toward intervening only when we have good evidence that our treatments will help.
 

Our bias should be toward not doing harm. Ignorance of the effects of our treatments is not a valid excuse for pushing a treatment.

Treatment for the sake of treatment benefits the person pushing the treatment – and only up until there is inescapable proof that the treatment is harmful.

That is the way medicine develops. We give treatments, based on wishful thinking and inadequate evidence. We find out that the treatments are more harmful than we thought. We abandon those dangerous treatments and make excuses for the harm.

Then we discourage recommend other treatments without good evidence – as if optimism is adequate justification for harming patients.
 

Since the papers I listed are not original research, but analysis of existing research, should the papers be excluded from this review?

Absolutely not.

Negative commentary is essential for pointing out the dangers of treatments.

When we are aggressive with any treatment, we need to be even more familiar with the dangers than the potential benefits.

–

Look at some of the rationalization employed to explain away the diversity of results. Diversity can be just the random variation of an ineffective treatment.
 

Compared with the ECASS III tPA-treated arm, the proportion with good outcome was somewhat lower and the proportion with mortality was somewhat higher, probably because patients in the SITS-ISTR registry had higher initial stroke severity and more medical comorbidities than the patients enrolled in the ECASS III trial.[2]

 

Probably?

If we begin with the bias that tPA is beneficial, that does make sense, but these are experienced researchers who should realize that it is critically important to minimize the influence of bias.

All of these authors receive money from the drug companies that will benefit from these guidelines. While money is not the only bias we should be concerned about, it should be fully disclosed and was not in this paper. Dr. Ryan Radecki wrote about this –
 

Three out of eight guideline writers directly involved with the pharmaceutical manufacturer. As far as indirect support, however, if they wanted to be more transparent, Dr. Edlow, Dr. Jagoda, Dr. Stead, Dr. Wears, and Dr. Decker also ought to have disclosed their association with the Foundation for Education and Research in Neurologic Emergencies – supported by multitudinous pharmaceutical manufacturers, including Genentech.

If you’re irritated that pharmaceutical manufacturers are helping write our clinical guidelines, make your voice heard.[3]

 

Being FDA approved is not the criterion for what is a good treatment. I probably write more criticizing FDA approved uses of drugs, than criticizing off-label uses of drugs.

–

Footnotes:

–

[1] Advertising unapproved uses of drugs is free speech, which is what the FDA has been trying to say
Wed, 05 Dec 2012
Rogue Medic
Article

–

[2] Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department.
This clinical policy is the result of a collaborative project of the American College of Emergency Physicians and the American Academy of Neurology.
Ann Emerg Med. 2013 Feb;61(2):225-43. doi: 10.1016/j.annemergmed.2012.11.005. No abstract available.
PMID: 23331647 [PubMed – in process]

Free Full Text Download in PDF format from Elsevier.

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[3] New ACEP tPA Clinical Policy
Wednesday, January 23, 2013
EM Literature of Note
Article

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Filed Under: Ethics, FDA, Heresy, Pharmacology, tPA

The Age of the Earth – Do Creationists have any clue about science? Part VIII

Sat, 24 Nov 2012 15:00:11 -0500 by
 

The anti-science comments of Marco Rubio are being defended as not affecting economics, as if economic impact determines the validity of science.
 

GQ: How old do you think the Earth is?

Marco Rubio: I’m not a scientist, man. I can tell you what recorded history says, I can tell you what the Bible says, but I think that’s a dispute amongst theologians[1]

 

There is some truth to that.

The only controversy over the age of the Earth is among theologians.

This is a controversy of religious ideology. This is not a controversy of science.

To present this as a scientific controversy is a lie.
 

Standing in front of the flag and telling lies is dishonoring the flag.
 

There are religious sects which claim that the Earth was formed 6,016 years ago.[2]

Based on the available historical information in 1654, this calculation seemed reasonable. It is no longer reasonable to ignore all of the evidence that contradicts these calculations.
 

and I think it has nothing to do with the gross domestic product or economic growth of the United States. I think the age of the universe has zero to do with how our economy is going to grow. I’m not a scientist. I don’t think I’m qualified to answer a question like that.[1]

 

The prudent response of someone who doesn’t have a clue about science should be to limit his response to I’m not a scientist. I don’t think I’m qualified to answer a question like that.

However, Marco Rubio is pandering to those voters who oppose science, so his response is a variation of the arrogant – I can choose my own reality. If I want to believe that the Earth is flat, or that vaccines cause autism, or that storks bring babies, I can ignore whatever evidence does not support my claim.

Marco Rubio is probably not qualified to comment on any of those. He may be smart enough to know that he doesn’t know enough about some of these topics, but he makes it clear that he is not smart enough to know just how little he knows about the age of the Earth.

This is a large part of what science is about – recognizing and eliminating potential bias.

We are all biased, but good science requires that we go to extremes to avoid having our biases interfere with research.

IST-3 was one horrible example of biased research having incompetent excuses made for the biases that should have been eliminated.[3] It isn’t science. The earlier tPA research is also biased. No patent should be given tPA based on such biased research.
 

At the end of the day, I think there are multiple theories out there on how the universe was created and I think this is a country where people should have the opportunity to teach them all.[1]

 

Theory or scientific theory?[4]

Misrepresenting the definition of scientific theory as just a theory is a fraud used by many who oppose science.

There is only one scientific theory out there – the Earth is billions of years old.

Where is there any scientific theory that the Earth is less than 4 billion years old?

There are a lot of unscientific theories proposed by preachers, but they have no scientific validity. It is only ignorance or deceit that allows Marco Rubio to suggest that these clams are in any way the equivalent of good science.

We should not have teachers making these absurd claims that reality is not real.
 

I think parents should be able to teach their kids what their faith says, what science says.[1]

 

The government should not be telling parents what to tell their children, but there is not any requirement that parents teach their children about reality. Marco Rubio is making a completely irrelevant statement, unless he is telling us that he has plans to have the government impose some such law on parents.
 

Whether the Earth was created in 7 days, or 7 actual eras, I’m not sure we’ll ever be able to answer that. It’s one of the great mysteries.[1]

 

There is no mystery.

Billions of years.

About 4 1/2 billion years.

The only mystery is why people keep listening to people claiming that religious controversies are scientific controversies.

Where is there any scientific evidence that the Earth is less than 4 billion years old?

We need to stop letting people lie to us.

No evidence means no valid claim.

 

Do Creationists have any clue about science? Part I

Do Creationists have any clue about science? Part II

Do Creationists have any clue about science? Part III

Shooting the messenger isn’t going to change the science – Do Creationists have any clue about science? Part IV

Do Creationists have any clue about science? Part V

Do Creationists have any clue about science? Part VI

Do Creationists have any clue about science? Part VII

The Age of the Earth – Do Creationists have any clue about science? Part VIII

–

Footnotes:

–

[1] All Eyez on Him
The junior senator from Florida had a heck of an election year: Short-listed for VP. Wrote a memoir of his Cuban heritage. Gave a tough, moving convention speech—maybe the best of its kind since Obama’s. Michael Hainey talks to Marco Rubio about growing up in the shadow of Castro, his love of Tupac, and whether he’s going to have an even better 2016
By Michael Hainey
December 2012
Page 2
Article

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[2] James Ussher
Wikipedia
Article

James Ussher (sometimes spelled Usher, 4 January 1581 – 21 March 1656) was Church of Ireland Archbishop of Armagh and Primate of All Ireland between 1625 and 1656. He was a prolific scholar, who most famously published a chronology that purported to establish the time and date of the creation as the night preceding Sunday, 23 October 4004 BC, according to the proleptic Julian calendar.

–

[3] Is a clot-busting drug safe for 6 hours after stroke symptom onset – or only for an hour and a half? – Part II
Wed, 14 Nov 2012
Rogue Medic
Article

–

[4] Introduction
Science and Creationism: A View from the National Academy of Sciences
Second Edition (1999)
National Academy of Sciences (NAS)
Page 2
On line version of book

Theory: In science, a well-substantiated explanation of some aspect of the natural world that can incorporate facts, laws, inferences, and tested hypotheses.
The contention that evolution should be taught as a “theory, not as a fact” confuses the common use of these words with the scientific use. In science, theories do not turn into facts through the accumulation of evidence. Rather, theories are the end points of science. They are understandings that develop from extensive observation, experimentation, and creative reflection. They incorporate a large body of scientific facts, laws, tested hypotheses, and logical inferences. In this sense, evolution is one of the strongest and most useful scientific theories we have.

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Filed Under: Creationism, Heresy, Science, tPA

Is a clot-busting drug safe for 6 hours after stroke symptom onset – or only for an hour and a half? – Part II

Wed, 14 Nov 2012 20:00:58 -0500 by
ResearchBlogging.org
 

It has been a couple of months since I wrote Part I and I have not been that motivated to write this part, but Dr. Jerome R Hoffman and Dr. Richelle J Cooper have been busy with the topic. Their paper appears in the current Emergency Medicine Australasia.
 

Just before the release of the results of the third inter-national stroke trial (IST-3),1 the largest trial of thrombolysis in acute ischaemic stroke (AIS), the journal Stroke published a remarkable pre-emptive strike – a commentary in which the author identifies a legion of concerns regarding the study’s methodology, only to reassure us about the study’s value.2 [1]

 

What Dr. Lyden appears to have been trying for is something like this:
 

Friends, Romans, countrymen, lend me your ears;
I come to bury IST-3, not to praise it.
The ICH that we cause lives after us;
The lysed clots are few and far between;
So let it be with IST-3. The noble Hoffman
Hath told you tPA is harmful:
If it were so, it was a grievous fault,
And grievously hath IST-3 answer’d it[2]

 

The result is inadequate.[3]

The response is another well deserved humiliation at the hands of Drs. Hoffman and Cooper.

This is not as bad as claiming that Hitler liked dogs, so he was really a good person who was just misunderstood. Still, this is a preposterous distortion of the scientific method and an abuse of the trust that we place in doctors.

IST-3[4] is flawed.

The use of tPA at any time before death to any patient who ever had a stroke, and maybe as late as at the funeral, is based on other flawed studies.

Dr. Hoffman continues –
 

In one astonishing section he lucidly catalogues a host of important biases likely to skew the study’s results in ways that increase the chance of finding a spurious benefit from the use of tissue plasminogen activator (tPA) – but then proceeds to trivialise the very concerns he has elucidated.[1]

 

Are these mistakes trivial?

Suppose you agree to treatment with a drug that should provide a benefit (based on this flawed study).

You later find out that the study was rigged.

The drug is really more likely to be harmful.

Would you call that trivial?

You now have a stroke from a clot and a bleed from tPA – and this isn’t even an episode of House, MD.

Trivial?

How trivial is your brain?

Epinephrine in cardiac arrest is similarly based on ignoring the harm to the brains of patients, so maybe the IST-3 authors just know good marks when they see them.
 

The author of this commentary – and by extension the editors of Stroke who approved it – ultimately concludes that despite its many flaws, there is much to learn from IST-3.2 We agree . . . although given that the actual results of IST-3 uniformly failed to show benefit, even in the face of severe bias, we believe the lessons are precisely the opposite of those being trumpeted by the study’s own authors.1[1]

 

That is enough of a preview. The full paper is available for free, so go read it.

IST-3 is an example of using a drug based on wishful thinking, surrogate endpoints, and flawed research, rather than based on valid evidence.

Our patients deserve better.

–

Footnotes:

–

[1] How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST‐3).
Hoffman JR, Cooper RJ.
Emerg Med Australas. 2012 Oct;24(5):473-6. doi: 10.1111/j.1742-6723.2012.01604.x. No abstract available.
PMID: 23039286 [PubMed – in process]

Free Full Text from Emergency Medicine Australasia

–

[2] Julius Caesar Act 3, Scene 2 – The Forum
Shakespeare homepage at MIT
Written by William Shakespeare (distorted for my own purposes).
Play

–

[3] In anticipation of International Stroke Trial-3 (IST-3).
Lyden PD.
Stroke. 2012 Jun;43(6):1691-4. Epub 2012 May 3. No abstract available.
PMID: 22556196 [PubMed – indexed for MEDLINE]

–

[4] The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial.
IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, Arauz A.
Lancet. 2012 Jun 23;379(9834):2352-63. Epub 2012 May 23. Erratum in: Lancet. 2012 Aug 25;380(9843):730.
PMID: 22632908 [PubMed – indexed for MEDLINE]

Free Full Text from PubMed Central.

–

Hoffman, J., & Cooper, R. (2012). How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3) Emergency Medicine Australasia, 24 (5), 473-476 DOI: 10.1111/j.1742-6723.2012.01604.x

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Lyden PD (2012). In anticipation of International Stroke Trial-3 (IST-3). Stroke; a journal of cerebral circulation, 43 (6), 1691-4 PMID: 22556196

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IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, & Arauz A (2012). The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet, 379 (9834), 2352-63 PMID: 22632908

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Filed Under: Ethics, Evidence, Heresy, Pharmacology, Research Blogging, tPA
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