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

- Rogue Medic

This is the Way to Bad Medicine – II

ResearchBlogging.org
 

A post at EM Literature of Note provides another example of bad research. Not just bad, but deadly.
 

The benefit of tPA in acute stroke is linked to the speed and degree of clot lysis and artery recanalization. 16 –18 [1]

 

Speed does appear to be most important. The debate about the efficacy of tPA (tissue-type plasminogen activator) for stroke is not that tPA will not be a good treatment when given within 90 minutes (1 1/2 hours). The debate is about the whether there is benefit when tPA is given between 90 minutes and 180 minutes (between 1 1/2 hours and 3 hours). The AHA (American Heart Association) quickly made it part of the guidelines to give tPA to as many patients with embolic stroke within 3 hours as possible. Some places have even expanded the fibrinolytic window to 270 minutes (4 1/2 hours).

If the AHA does the same with this proposed treatment, our stroke patients might be better off if we took them to hospitals NOT equipped to treat strokes.

Why?

Let’s look at the study –
 

Purpose
The primary purpose of this study was to assess the safety of combined Argatroban and tPA in ischemic stroke as measured by the incidence of significant intracerebral hemorrhage (ICH). The secondary objective was to evaluate drug activity by determining the speed and completeness of arterial recanalization and reocclusion.
[1]

 

The primary purpose of this study is to determine safety.
 

Safety was defined as a rate of symptomatic ICH or Parenchymal Hematoma Type 2 intracranial hemorrhage not exceeding 10%. We hypothesized that a hemorrhage rate of 10% might be acceptable only in the setting of significant increases in arterial recanalization, which is highly associated with improved clinical outcomes. [1]

 

Highly associated with?

I love treatments that are highly associated with some surrogate endpoint, because that is what matters to the patient.

We achieved the surrogate endpoint. That surrogate endpoint is highly associated with improved outcome. Therefore, you’re cured. Don’t try to speak to thank us. Just trust us.

You are cured.

Your inability to speak is probably just a conversion disorder – and don’t try to get up. You are cured, but your inability to walk is probably just psychological. It’s all in your head.

Too much sarcasm? Am I being unfair? Keep reading.
 

All patients received intravenous tPA (0.9 mg/kg). There was no delay in starting intravenous tPA as a result of participation in this study. Informed consent and other qualifying activities for the study took place after the intravenous recombinant tPA bolus was given.[1]

 

This is good. There is no change that affects the initiation of the standard treatment.
 

(3) baseline NIHSS score 17 (modified to 15 after the first 15 patients) for right hemisphere and 22 (modified to 20) for left hemisphere strokes;[1]

 

Why modified?
 

The first 2 significant hemorrhages occurred with NIHSS scores of 15 and 21 (both right MCA strokes), prompting the data and safety monitoring board to reduce the upper limit of the NIHSS score to 15 (right hemisphere) and 20 (left hemisphere).[1]

 

The lower the NIHSS (National Institutes of Health Stroke Scale[2]) number, the less serious the stroke. Scores range from 0 to 42, with higher being worse, so these are not severe strokes. How much improvement is worth to each patient vs. the risk of worse neurological injury, or death, is difficult to state. Looking through the grading, very intoxicated might score around the 13 average for the patients in this trial. I would not classify that as mild.
 

A total of 32 serious adverse events occurred in 22 patients (see Table 3).[1]

 


 

I do not know why they calculated these as percentages of the serious adverse events, rather than according to patients treated.

If you develop a serious adverse event, you have a 21% chance of death.

They appear to be assuming that this ratio will persist across serious adverse events, which is not a reasonable conclusion. This is just a derivative of what I want to know. What I want to know is –

If I receive the treatment, what are my odds of death, disability, et cetera.

Their categorization of only 3 (out of 32) serious adverse events as Probably related to treatment and none as Definitely related to treatment suggests that they are not being objective. How do they explain this in the discussion? They don’t. Maybe they aren’t referring to the serious adverse events, but are referring to deaths. I don’t know and since they do not explain, I can only speculate.

We know that tPA increases the risk of bleeding. We expect that giving an anticoagulant (argatroban is a thrombin inhibitor) with tPA increases that risk of bleeding. We conclude that the bleeding in our patients is just a coincidence, because that’s the way we roll, Yo!

You had a thrombotic stroke, but now you have so much bleeding that your brain is squeezing out through any orifice possible. This is just one of the improbably large number of coincidences during this study.
 

On discharge, 76% of patients went either home or to acute rehabilitation, and 7 patients died (10.8%). Five of the 7 deaths resulted from large hemispheric infarction with herniation, whereas the other 2 died from respiratory failure. Six of the 7 deaths occurred after the family requested withdraw of care.[1]

 

Six of the 7 deaths occurred after the family requested withdraw of care.

I don’t know if they are just providing complete information or suggesting that the deaths are the fault of the families for not trying to keep their family members alive in nursing homes with zero quality of life.
 

long enough to prevent any reocclusion. 12 However, 3 of our 4 significant hemorrhages occurred 18 hours into the infusion. A 12- to 18-hour infusion might produce even safer and equally effective results.[1]

 

However, shortening the infusion to zero hours might produce even safer and equally effective results.
 

What does Dr. Radecki say about this trial?
 

Because NIHSS score predicts bleeding, we can compare to the NINDS trial TPA group, whose median NIHSS score of 14 compared with this trial’s median of 13. The NINDS trial showed a 10.8% rate of ICH and about 4% mortality at 7 days.[3]

 

3 dead patients would have been 4.6%.

There were 7 dead – 10.8%.

Is it safe?

I guess that depends on how much life insurance you have on the person being treated and how much you dislike them.
 

These rates of bleeding are of the same order of magnitude seen with intravenous recombinant tPA alone and therefore low enough to justify further evaluation in more patients to arrive at a more confident assessment of the true risks of bleeding.[1]

 

What is their point?

What if . . . ?

What if this really is beneficial? We wouldn’t want to miss out on this potentially useful, although potentially very dangerous, treatment.

They are ignoring the risks. The question, What if . . . ? can also be reversed –

What if the adverse events in this group are statistically much lower than what we should expect if we were to treat a large number of patients?
 

Do the authors understand the risks they are subjecting patients to?
 

Higher doses of Argatroban might also be safe and even more effective, but this will require careful evaluation.[1]

 

Maybe the patients had all of these bleeds because we gave too much of our study drug that causes bleeding, but we aren’t going to rule out the possibility that we did not give enough.

Is this really that much different from presuming that blood-letting is not working because of not taking enough blood?[4]
 

Further study of this treatment combination appears warranted.[1]

 

No.

 

I hope that no IRB (Institutional Review Board) is ever impaired enough to come to the conclusion that this should be expanded to harm more patients.

Earlier, I asked if I was using too much sarcasm, but now I think I may have been too subtle. What do you think.

Footnotes:

[1] The Argatroban and Tissue-Type Plasminogen Activator Stroke Study: Final Results of a Pilot Safety Study.
Barreto AD, Alexandrov AV, Lyden P, Lee J, Martin-Schild S, Shen L, Wu TC, Sisson A, Pandurengan R, Chen Z, Rahbar MH, Balucani C, Barlinn K, Sugg RM, Garami Z, Tsivgoulis G, Gonzales NR, Savitz SI, Mikulik R, Demchuk AM, Grotta JC.
Stroke. 2012 Jan 5. [Epub ahead of print]
PMID: 22223235 [PubMed – as supplied by publisher]

[2] NIH Stroke Scale
NINDS
PDF Download of Stroke Scale with explanations of scoring

[3] Helping TPA Help Patients Bleed
Wednesday, January 25, 2012
EM Literature of Note
Article

[4] Answer to What is this Dangerous Treatment and How Long Did it Take to Stop Using it
Wed, 01 Feb 2012
Rogue Medic
Article

Barreto, A., Alexandrov, A., Lyden, P., Lee, J., Martin-Schild, S., Shen, L., Wu, T., Sisson, A., Pandurengan, R., Chen, Z., Rahbar, M., Balucani, C., Barlinn, K., Sugg, R., Garami, Z., Tsivgoulis, G., Gonzales, N., Savitz, S., Mikulik, R., Demchuk, A., & Grotta, J. (2012). The Argatroban and Tissue-Type Plasminogen Activator Stroke Study: Final Results of a Pilot Safety Study Stroke DOI: 10.1161/STROKEAHA.111.625574

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Comments

  1. I read the article on Bad medicine and let’s just
    Say eight weeks ago I new absolutely nothing about
    Srokes,NiNDS trials TPA or anything else that goes
    Along with it.My father suffered a mild stroke a 5 on the
    Stroke scale my poor father made the mistake of getting to
    The hospital early.I mean isn’t a hospital where to go when
    You feel there is something wrong with you.My father was 59
    Years old normally fit and healthy.He was suspected of suffering
    A posterior circulation stroke.As it turned out my father was a candidate
    For TPA.At 4 hours of onset he received that lethal injection.2 hours later
    Suffered a massive brainstem haemarrage.They then palmed him off to a so called better
    Hospital.Where of coarse they could do nothing for him.And what took the cake he spent the
    Last five days of his life locked in.When on day five he died with the last bit of dignity he had left. I read of this wonder drug
    For ischeamic strokes.I know I’m not a Naerologist but I don’t think you have to be to realize that drug is
    Bad news and the fact it is justified with these minimal studies is even more insulting.My father was a great man, not a lab rat.

  2. Now 7/12 months on.I had to take my mum to hospital suffering chest pain.Of coarse being a result of the hell the poor woman has had to live the past few months.and let’s just say the toll of this hasn’t exactly been super easy for myself and my brothers.Let’s just call it something simple like HELL.
    Of coarse I’m going to air on the side cation.It just so happens the nurse at hand, is also a nurse at the in my opinion the hospital that made the fatal call to administer my father with that toxic drug TPA.I told her our wounds are roar after all he came here first and then went to that hospital.She had the nerve to say to me that’s a shame that drug does wonders for stroke.I then naturally replied have you seen it work,she said no I’ve Just heard.I guess I kind of Just saw red then.Please don’t get me wrong I strongly believe that Nurses are a hospitals back bone.Without them we are seriously f#d.But truly honestly how screwed is this world.My mother who now is sick with a heart condition.I call it broken heart.My brothers who are ruined,me who has two young kids and I’m up at this hour writing this should tell all all are seriously broken.Broken because of this drug TPA.I can’t believe all it takes is line my pockets a little and its approved.My God if there is one.What ever happened to Doctors cause no harm!!!

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