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

- Rogue Medic

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

ResearchBlogging.org

The clot-buster tPA (tissue Plasminogen Activator) is given to stroke patients within 3 hours of onset of symptoms (some use 4 1/2 hours), based on a poorly done study. Some doctors are claiming that the benefits from tPA for stroke can be extended even to 6 hours.

Are the authors exhibiting stroke-like symptoms from sipping too much of their own Kool-Aid?

My first experience with a patient being given tPA for stroke was over a decade ago with a patient I brought to the hospital within about 45 minutes of symptom onset. The criteria for treatment were a negative CT (Computerized Tomography) scan for intracranial bleed, ruling out other bleeding risks, and a maximum of 3 hours from witnessed symptom onset.

The biggest delay was supposed to be the time it takes to get the CT scan. The neurologist was there, read the scan – all within an hour and a half of symptom onset, and then waited

and

waited

and

waited

and

– at 2 hours and 55 minutes from the onset of symptoms – the neurologist gave the order to begin treatment.

tPA is not an all-or-nothing drug. This isn’t a movie, where the hero can receive an antidote a few seconds before a poison would kill him, and he is unharmed. Damage is cumulative, and often permanent. The possible benefits decrease with time, while the side effects don’t have much reason to change with time. Damage to the brain does not magically go away.

If I want to take a hot shower, I want to run the water just long enough to get the water hot, but not so long that I run out of hot water. The amount of remaining hot water decreases the longer I wait. There is nothing wrong with cold showers, but if the goal is a hot shower, that is the wrong way to accomplish the goal.

With a stroke, the goal is appropriate treatment as quickly as possible, because the longer the ischemic part of the brain is ischemic, the worse the outcome. The benefit runs out over time.

The NINDS (National Institute of Neurological Disease and Stroke) trial, that led to the original rush to make tPA the standard of care, was the response to smaller studies that showed mixed results with use of tPA.

These results were enough to justify further investigation in the form of a larger, randomized, placebo-controlled trial.[1]

So, thousands of patients were enrolled in this huge stroke trial was begun. OK, there were 614 patients enrolled. Part 1 only looked at improvement 24 hours later. That may be the ROSC of stroke care – nice, but irrelevant if that is all we get. There were only 333 patients in the part that mattered – Part 2. Only 168 received the study drug in Part 2. But Part 2 was broken down into 0-90 minutes from symptom onset to treatment initiation and 91-180 minutes. There is no real controversy about using tPA within 90 minutes of symptom onset. The controversy is with treatment from 91 to 180 minutes (1 1/2 hours to 3 hours).

Only 82 patients received the study drug in Part 2 that time period. Maybe the Part 1 patients should be included, since their results are included by the authors, but that is still only 168 patients.

We need to be careful of drawing big conclusions from small numbers. These are small numbers representing a diverse patient population.

The primary hypothesis for part 2 was that there would be a consistent and persuasive difference between the t-PA and placebo groups in terms of the proportion of patients who recovered with minimal or no deficit three months after treatment.[1]

The results reported suggest that this is what happened, but as more information has been released about the study, it has become apparent that the patients in the treatment group were much healthier than patients in the placebo group.
 


Picture credit.
 

Some people who want to get rich will trade on the futures market. How do you make a million dollars on the futures market? Start with two million dollars. Your two million dollars will soon become one million dollars.

The authors appear to have a similar philosophy. One way to make a drug look good is to compare it to a drug that is worse. In a placebo trial, that may not be possible, so the way to make an ineffective drug look good is to put the sicker patients in the placebo group. Even a dangerous drug will not look so bad by comparison.

Did the authors hide the difference in stroke severity intentionally? It doesn’t matter. The authors did not make it easy to get the relevant information.

tPA is a treatment that has become standard of care without good evidence.

The AHA (American Heart Association) has also been pushing this poorly studied treatment aggressively with mandatory content in their courses on treating heart problems.
 

The problems with the study have not gone unnoticed.

Dr. Jerome Hoffman wrote –

Another concern is that, in the 91-180 minute group, patients who received placebo were much sicker at baseline than those treated with tPA. Sicker patients tend to have worse outcomes, and these baseline differences may explain much of the apparent benefit that has been attributed to tPA. These problems make it unclear whether there was any benefit to the use of tPA. If so, it is almost certain that the time limit for benefit is far less than 180 minutes, and perhaps much closer to 90 minutes.[2]

 

Dr. Jeffrey Mann wrote –

In summary, the recommendations for the use of tPA in patients with acute ischemic stroke were based on an initial misinterpretation of the results of the NINDS trial and are, therefore, unwarranted.[3]

 

In defense of the lack of research, Dr. Patrick D. Lyden, one of the NINDS investigators, writes –

The limitations on this therapy—the only proven stroke treatment—are legendary: patients must be treated promptly after stroke onset, must have no contraindications to thrombolysis, and must be treated by a team skilled in preventing potential complications. Much has been made of these limitations, to the point of considerable nihilism among neurologists. Yet, results similar to the NINDS data are obtained in communities with active stroke teams dedicated to proper use of intravenous thrombolysis.[4]

 

Is the study just misunderstood?

Is tPA really a hooker with a heart of gold?

Results Seventy patients (1.8%) admitted with ischemic stroke received IV tPA. Of those, 11 patients (15.7%; 95% confidence interval [CI], 8.1%-26.4%) had a symptomatic ICH (of which 6 were fatal) and 50% (95% CI, 37.8%-62.2%) had deviations from national treatment guidelines. In-hospital mortality was significantly higher among patients treated with tPA (15.7%) compared with patients not receiving tPA (5.1%, P<.001) and compared with the model's prediction (7.9%; P<.006).[5]

 

Only half of the patients treated met the treatment criteria for tPA.

The in-hospital death rate was 5.1% without tPA.

The in-hospital death rate was 15.7% with tPA.

This is what Dr. Lyden is defending.

That paper was published before Dr. Lyden’s editorial

Dr. Lyden finishes with an absurd statement –

Perhaps we will find a way to treat patients later than 3 hours, and further studies are needed to push the outer limit of the time window, but within the 3-hour window, no further trials are needed; the drug works. The dictum primum no nocere still applies: we must do no harm, either by actively committing an act or by withholding a proven therapy through inaction.[4]

 

We have too many doctors defending too many poorly studied treatments.

Primum non nocere means first, do no harm.

Giving a poorly studied treatment, while claiming that it would be unethical to learn more about the treatment, is dangerous to the patient.

Giving a poorly studied treatment, while claiming that it would be unethical to learn more about the treatment, corrupts our ability to think rationally.

Giving a poorly studied treatment, while claiming that it would be unethical to learn more about the treatment, corrupts our ability to think ethically.

IST-3[6] is an attempt to extend the treatment window for tPA to 6 hours. I will write about that later. This was just to set the stage and introduce some of the cast of characters.

When treating cardiac arrest, we try to minimize the amount of damage from reperfusion, but with stroke we only seem to be trying to minimize re-examination of a treatment that never should have become the standard of care.

Continued in Part II.

Footnotes:

[1] 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 NEJM.

[2] 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 – in process]

Free Full Text from CJEM.

[3] 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]

Free Full Text from PubMed Central.

[4] Further randomized controlled trials of tPA within 3 hours are required-not!
Lyden PD.
Stroke. 2001 Nov;32(11):2709-10. No abstract available.
PMID: 11692041 [PubMed – indexed for MEDLINE]

Free Full Text from Stroke.

[5] Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience.
Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hinchey JA, Hammel JP, Qu A, Sila CA.
JAMA. 2000 Mar 1;283(9):1151-8.
PMID: 10703777 [PubMed – indexed for MEDLINE]

Free Full Text from JAMA.

[6] 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.

NINDS researchers (1995). Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. The New England journal of medicine, 333 (24), 1581-7 PMID: 7477192

Hoffman JR (2001). Thrombolytic therapy for acute ischemic stroke – Tissue plasminogen activator for acute ischemic stroke: Is the CAEP Position Statement too negative? CJEM, 3 (3), 183-5 PMID: 17610781

Mann J (2002). Truths about the NINDS study: setting the record straight. The Western journal of medicine, 176 (3), 192-4 PMID: 12016245

Lyden PD (2001). Further randomized controlled trials of tPA within 3 hours are required-not! Stroke; a journal of cerebral circulation, 32 (11), 2709-10 PMID: 11692041

Katzan IL, Furlan AJ, Lloyd LE, Frank JI, Harper DL, Hinchey JA, Hammel JP, Qu A, & Sila CA (2000). Use of tissue-type plasminogen activator for acute ischemic stroke: the Cleveland area experience. JAMA : the journal of the American Medical Association, 283 (9), 1151-8 PMID: 10703777

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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Comments

  1. I’ve read all there is to read about TPA these past 4 months.What it is in my opinion as a daughter
    A mother a sister,not a mechanical Neurologist who thinks because
    They have studied brain think they know it all.I know first hand what
    This drug does it takes a mild stroke patient and it ends
    There life in the the worst possible way there is.Now I’m not saying
    It doesn’t have a use besides cardiac or blood clots. I think it would be perfectly matched with death sentence prisoners.I mean isn’t that the aim of this drug company and the sell outs who endorse it.
    Ha stroke so expensive!!We have no cure.TPA comes along yes we care we have a whole shit load of
    Studies for this wonder drug that treats ischemic strokes.Yahh Money saved money made baby.And let’s just screw the families who lose there love ones.I mean who cares our pockets are lined.And for those who are left to visit a grave of a young man who other wise would be alive if not for this drug.I have this for us as a family. BROKEN,CRUSHED ,Destroyed,angry,hurt.My god I could go on.The suffering we faced as a family because of this drug is to much to bare.I will not stop with this I promise.

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  1. […] 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 […]

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