Why we should be very wary of using clotbusting drugs to treat acute strokes

This is Part 1 of two posts

  1. a basic overview of thrombolysis in stroke
  2. a detailed overview of  evidence based research into thrombolysis and CVA

Author: Prof Daniel Fatovich

Let’s compare the treatment of strokes, to the treatment of heart attacks. Heart attacks are caused by a sudden blockage of a blood vessel supplying oxygen to heart muscle. This is nearly always caused by a new blood clot that forms on a hardened and diseased blood vessel.

Background

It took trials and studies on 60 000 heart attack patients to work out that clot busters prevent deaths in heart attacks, but that they only worked on one type of heart attack (which is only about 5% of all heart attacks). So we took the time to get it right, refining study after study, until we were sure that introducing a potentially dangerous drug had benefits that outweighed the harms.

Every type of clot buster that was studied worked, and the earlier it was given, the better. Interestingly, the one that caused the most brain bleeding was tPA.

Studies have been done on clot busters in stroke. Strokes are also caused by a blockage to a blood vessel (in the brain), but there are important differences to heart attacks:

  1. About 30% of the time, the cause of the blockage is never worked out.
  2. There are two very different types of blood clots that cause strokes: new blood clots (like in heart attacks) & old blood clots (eg an old blood clot that has formed in the heart & travelled to the brain & blocked off a blood vessel) – called embolic clots.
  3. This difference between new & old blood clots is very important, because clot busters do not work on old blood clots.
  4. How many strokes are caused by new blood clots? No one knows for sure because we can’t work out what kind of clots (or other causes) are causing the stroke. The best guess is that it is a little less than half.

“It is important to note that the efficacy of thrombolytic drugs depends on the age of the clot. Older clots have more fibrin cross-linking and are more compacted; therefore, older clots are more difficult to dissolve. For treating acute myocardial infarction, the thrombolytic drugs should ideally be given within the first 2 hours. Beyond that time, the efficacy diminishes and higher doses are generally required to achieve desired lysis.” [Reference: CV Pharmacology Thrombolytics]

Things you need to know about the stroke clot busting studies:

  1. There are 12 important studies: 10 were negative (ie they showed that clot busting did not work in stroke). Of these 10 studies, 4 had to be stopped early because of harm ie they were killing people. So far, they have only studied this in about 1/6th the number of stroke patients compared to the heart attack studies.
  2. This is a completely different situation to the heart attack studies, where it worked in every study & every clot busting drug they tried worked.
  3. The 2 positive stroke studies (ie they suggest a statistical benefit) have been widely criticised in the medical literature because of their scientific flaws. One of these 2 studies looked at giving tPA within 3 hrs of the stroke. Interestingly, this study proved that there was no benefit in the first 24 hrs, which again, is different to the heart attack studies. The other study looked at giving tPA from 3-4.5 hrs after the stroke. This second study also contains some major errors.
  4. The biggest flaw is that there was an imbalance in baseline stroke severity. The placebo group(those that didn’t get tPA) were sicker, with more severe stroke; the tPA group were less sick & had much more mild strokes. Everyone understands that people with milder strokes do better than people with more severe stroke. So obviously, the study favoured tPA, because the tPA group had milder strokes, which will do better anyway.
  5. This study was re-analysed later. If tPA really worked to improve the outcomes in sudden stroke, then there should be a much larger improvement in outcome compared to the placebo group.  But there was no difference.
  6. The studies show that tPA causes brain bleeding in about 6% of patients. Brain bleeding is the other type of stroke. It is strange that some people would advocate a treatment for stroke that can cause a (worse) stroke. Brain bleeding is very severe, and if this happens, almost half the people die.
  7. Why does brain bleeding happen with a clot buster? Doctors think of clot busters as being like ‘drano’, a plumbing product that is used to unblock pipes. In strokes, you have a damaged blood vessel inside a damaged part of the brain. So if you put ‘drano’ in there, it’s no surprise that it sometimes dissolves through the blood vessel & bleeds into the brain.
  8. The largest study on clot busting in stroke was published in 2012. This again was a negative study ie it showed that tPA did not work, but confirmed the increase in early deaths with tPA.
  9. Interestingly, the time to give the drug from the stroke studies is completely different to the heart attack studies. In heart attacks, after studying 60 000 patients, every study showed that the earlier the clot buster was given, the better. In the stroke studies, the majority of the studies do not show this effect. The reason for this is unclear, but may be because the patients who get to hospital earlier are somehow different to the ones who arrive later.
  10. However, one must always remember that once the blood vessel is blocked, the brain cells will be dead in about 3 min. So giving a clot buster later shouldn’t have any effect, & this may be what we’re seeing. It’s also worth remembering that heart muscle cells & brain cells are very different.
  11. People have used statistical techniques (called meta-analysis) to ‘prove’ that clot busting works. The simple summary of the problem with this, is that garbage in = garbage out. Badly done studies, when put into a meta-analysis, do not magically become good studies. There is at least one review of this that concludes: “there is no consistent or proven benefit” to clot busters in stroke. [Reference: Thrombolytics for Stroke]

What is the problem here?

Why is there controversy in the medical world? Shouldn’t it be black and white? Either tPA works, or it does not.  Easy.

Sadly it is not so easy.  Statistical analysis of any medical treatment is rarely black and white. It is about the interpretation of the research. This is where the controversy has occurred here.

So why is this being pushed? 

  1. We really want it to work.
  2. Unfortunately, many of those pushing this treatment have conflicts of interest with the manufacturer of the drug. [Reference: Why we can’t trust clinical guidelines and Ensuring the integrity of clinical practice guidelines]

So how do we resolve this problem?

  • We think that patients, & society in general, expect that an offered medical treatment will have passed the test of science. The test of science requires: elimination of bias, healthy scientific debate, & replication.  Replication means repeating the study that suggested a statistical benefit, to see if we can get that result again, which would make it more believable. Time & time again, in medical research we find that when larger more decisive studies are done (ie replication) the initial exciting result becomes a disappointing one – it doesn’t work. This replication has not happened for stroke, but needs to, if we want to maintain our trust in medicine. [Reference: Do risks outweigh benefits in thrombolysis for stroke?]

Has anyone else raised concerns about this?

So is there anything else that can be done if I have a stroke?

We know that having your care in a stroke unit is much more powerful than any drug. And taking part in stroke research will help us to answer these unanswered questions.

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Comments

  1. Joe says

    So is there anything else that can be done if I have a stroke?

    >> Thrombectomy isn’t mentioned at all -- in certain kinds of stroke (large vessel occlusions) it’s been shown to be much more effective than thrombolytics.

    • Judson says

      Wrong. See the 3 studies just released this summer on thrombectomy. The largest one was stopped early because they could show no benefit in outcome despite high rates of vessel patency (80%vs 40% with tpa).

  2. Pik Mukherji says

    I have said these things. And yet, somehow when it comes out of my mouth there is less clarity and a mixture of indignation and confusion. I’m just going to send the med students a link to this post.

  3. says

    Thank you for keeping at this fight along with Dr. Newman and others. I think it’s important that everyone understands this isn’t about whether or not thrombolytics “work” for stroke. In fact, wherever you fall, it’s hopefully clear at this point that even if they “work,” they don’t work very well. (This doesn’t mean we shouldn’t use them — you could say that they don’t work very well for STEMI, but they clearly do WORK, so it’s a valuable therapy — but it does demonstrate how this isn’t exactly a fight for big stakes.)

    The key point is that there IS equipoise on the issue, which is not what most supporters of lytics like to believe. And this should go both ways: although I have my doubts, it is not unreasonable to believe they do work. A reasonable, intelligent, well-informed clinician can believe in either position, but he really cannot believe that his position is utterly beyond debate; he cannot believe that he knows the truth and it’s clearly supported by the evidence. And it’s disingenuous to address either fellow providers or patients without acknowledging this uncertainty.

  4. Mark Fisher says

    Superb work, Michelle. I have often wondered whether there might be an ethical (and ?potential medico-legal) obligation to actively oppose such treatments.

  5. John says

    What the president of the Stroke Society of Australia has to say…..

    Dear SSA members

    There is a program related to acute stroke treatment airing this Tuesday evening (8.30 pm AEST) on SBS (Insight).

    http://www.sbs.com.au/insight/episode/overview/579/Strokes#.UlDzc6W4Zjp

    A number of our members will be featured as well as some stroke patients with very interesting stories. Unfortunately, during the recording there was also some air-time given to a minority group of tPA-sceptic Emergency Physicians, who despite a huge body of evidence, still claim we should not be treating eligible patients with this proven therapy.

    There will be an opportunity to respond via Twitter as the program goes to air live. We need as many people as possible to respond along the lines that this small, but vocal minority of emergency physicians are the medical equivalent of climate-change sceptics, and by their actions they deny stroke patients a proven, highly effective treatment. If you do not have one, please consider setting up a Twitter account and ask as many people as possible you know to watch the program and respond via Twitter.

    Kind regards

    • says

      Thank you John.
      Open debate is welcome. Our stance would never be to deny any patient a proven therapy. The posts have been about the interpretation of the evidence to date, and to question whether, on current scientific standards, this therapy truly is ‘proven’. Like you, I have no doubt that this will not be solved by a television show.

    • says

      Anyone who has read the stroke literature knows that neurologists are prone to hyperbole but surely this has to be a joke. On the other hand, where does the Stroke Society of Australasia get their funding from?

      • Wombat says

        I couldn’t tell you where their funded, but what I will say is that over the last ten years I’ve spent working as a Paramedic in Melbourne, Australia, the way we treat strokes has changed dramatically, and the much better outcomes from this treatment, have come down to two factors -- early diagnosis, and early treatment via thrombolytic drugs. We have a state-based healthcare system, with very clear guidelines concerning time-frames from onset of symptoms, appropriate treating facilities & other factors, such as the patients co-morbidities.

        When the ‘starts align -- Young-ish patient (under 80), early diagnosis both at the patients residence & then via CT scan at hospital & transport to an approved hospital, then thrombolytic drugs have an incredibly good effect. The timeframes tend to be that thrombolysis is needed within about 3 hours -- much beyond this & the outcomes are not as good, to the point it’s not recommended beyond ~6hrs. But, newer drugs are being experimented with that will eventually (hopefully) extend this window of opportunity.

        I suspect the poor results seen in the studies you’re looking at are perhaps because the drugs have been administered somewhat indiscriminately. When given to a select group of patients, that have good chances of doing well -- those patients tend to do well. It’s a risk/benefit analysis prior to treatment.

        That said, I think the ‘new frontier’ for strokes is thrombectomy -- we’ve had a small number done & the results are very promising. Vessel sive & access is an issue, but so it once was with cardiac thrombectomy & stenting. Technology changes & outcomes change…..

        • says

          Here is the problem: you believe you are having better outcomes by using tPA, but don’t really know.

          Do a prospective randomized study and compare results. That would help to settle this question.

  6. says

    And after a very bruising program, I would be keen to ask any tPA proponents why they supported the use of anecdotal ‘successes’, and the fact that patients were cured on the end of a needle, when in fact, every single piece of evidence shows that if there is going to be any improvement post tPA it is only at 30 days -- there is no difference between tPA and placebo in the first 24 hours. Other than that, I now leave it up to the hands of the thinking medical fraternity and public.

  7. says

    Greetings from Chile!
    Here we are seeing neurology specialists very excited with tPa, and they are starting to use it in virtually everyone that meet the inclusion criteria on the NINDS study, and they are using the 4.5 hours as time frame (fortunetly they aren´t more than 10% of the strokes). Thay are trying to push this drug even in our public health hospitals, where usually the conditions necesary to use this drug aren`t the ideal. I understand they are really trying to benefit the patients, but I think they are doing it the wrong way. Why not invest all that tpa money in stroke units! we don´t have them, they are harmless for our patients and they are proven to work and make the outcomes better. I guess that they aren´t sexier as pushing ev a pricey drug that can make your brain bleed!
    As David Newman says in last EMRAP chapter (november), it´s understandable that the doctors that lead this trials have wishful thinking on tPa, but in order to use it in every day bases, we need more than that. We need an appropriate analysis of the evidence available, and today, that analysis suggest that we shouldn´t use tPa for every patient. If we do so, we are doing more harm tha good to them.
    Our group of neurologist have a very interesting approach. If a patient with symptoms of stroke arrive to our ED within the time frame (4.5h), they always start with angioCT. If there is evidence of occluded vessel, they start with a mixed thromolytics protocol (iv + intrarterial) + mecanical thrombectomy, I haven´t seen iv tpa alone. If they don´t see evidence of an ocludded vessel, they don´t push tpa. Food for thought.
    Good bye from the south of the worl, Santiago, Chile
    Nico

  8. says

    Wow. Just wow. Good summary Michelle….and interesting comment from President of Stroke Society Australia.

    I’m going to hark back to the etymology of ‘stroke’.

    In olden times, folk would head off into the forest to chop wood (or till the fields, or thatch huts etc)….and then become struck down with hemiparesis or dysphasia.

    In the absence of an obvious wound, the obvious was that these injuries were inflicted by the fairy folk -- hence the term ‘elf struck’ -- to become “stroke”

    Seems similar magical thinking afflicts the SSA.

    Face it, there is equipoise. Name calling (equivalent of climate change sceptics) when there exists uncertainty is not good science.

  9. A. Franklin says

    I do not understand the fascination generalists have with trying to analyse subspecialty expertise, as though complex debates can be settled by a physician who sees only acute presentations, is witness to only immediate (not delayed) complications, and has little grasp on long term follow up nor has the time to properly analyse literature (this is not a criticism -- if I had a wider specialty I would not be able to keep up either!). I love my ED colleagues, but some (such as this author), overstep the bounds of their expertise.
    While my ED colleagues to raise reasonable concerns, this article is poorly written, misreads significant bodies of evidence, over-relies on TheNNT.com, and seems to be stuck in the late 90’s/early 00’s, when yes, we didn’t really know how to use thrombolysis in acute stroke effectively.
    The criticisms raised in this article are nothing new, but probably reflect bias against thrombolysis, as much as they accuse us of being biased for it. Importantly, this is an article written for laypeople, so I do concede it is somewhat simplified and may not carry the author’s full weight of intellectual thought, but it does raise a few important points.
    1. The studies
    Yes, there has been difficulty proving stroke lysis works. There is reason for this. In the early days, we did not really know who it would work in. Early negative trials tended to have thrombolysis given very late (ie. beyond a few hours). Given what we know now, it is not surprising at all that thrombolysis 6-9 hours down the track is not effective.
    Take for example the recent IST-3. This demonstrated no mortality benefit, but did show a significant shift of morbidity in favour of thrombolysis. Importantly, it did not demonstrate any mortality cost. That is, if your stroke is going to kill you regardless, thrombolysis just shifts that forward in time a bit. Now, if you or I were to have a large dominant TACI, would you prefer to die within 7 days or 6 months? And if you survive, would you like to be able to walk, or remain bedbound?
    What about the opportunity cost? What if we do say, ok, thrombolysis is not the best drug every used…what then?
    Strokes are terrible. They are hands down, worse than STEMI. Comparing to the cardiology literature is a useless comparison. There is no comparison with myocardial infarction. If I had to choose, I’d take 5 STEMI’s over a TACI. I am clearly biased, but I struggle to imagine a worse acute medical diagnosis -- most malignancies have a better prognosis! Ever cautious about doing something just because, still I feel doing nothing is more harmful. Every percentage point of improvement, especially on measures such as disability, is important. Mortality itself is not a useful outcome to measure in stroke, aside to check you’re not actively killing people.
    Shifting mortality to earlier in the piece, to allow a proportion a better recovery, is worthwhile.
    6. Brain bleeding
    I’m not sure what point the author is trying to make. We know that around 10% of ischaemic stroke haemorrhagically transforms, even in the absence of thrombolysis. We just don’t take any notice because we carry on with aspirin and don’t re-scan unless they deteriorate.
    Of course thrombolysis carries risk of bleeding -- it does in the MI trials too -- but it is related to stroke severity. In fact, there is good literature from the Scandinavian countries, where thrombolysis in healthy brains had no effect, and minimal risk. So, given the risk of bleeding is highest in those with the greatest risk of poor outcome -- ie. they are going to die or be severely disabled -- a small excess bleeding risk is acceptable. Not ideal, but acceptable.
    8. IST-3
    I’ve mentioned this article above, but clearly the interpretation of this trial is flawed. IST-3 was not a negative trial, nor does early mortality, in the context of no excess mortality risk, represent a concern.
    10. 3 minutes for brain cells to die
    Of course, thrombolysis is not given to save the dead brain, it’s for the penumbra, which is* salvageable and **is worth saving. This point is so ludicrous as to border on emotive blackmail to laypeople.

    • says

      Thank you Dr Franklin for your comments

      We greatly appreciate and value the considered opinions of experts in the area of stroke management, and you make some very valid points.

      Please note that the post author has gone on to evaluate additional papers and provide a measured overview in the second post in this series over at http://lifeinthefastlane.com/use-thrombolysis-treatment-acute-stroke/.

      Generalists are interested in the evidence base for specialised acute intervention for many reasons, in this case it is of specific interest as this primary intervention (thrombolysis) is often administered within our emergency departments. We like to be furnished with high quality research and evidence based knowledge on this and many other medical concerns in order that we may provide assistance in the acute management of these difficult situations.

      I believe we are all on the same page -- we want the best possible outcome for our patients, their families and society in general. Believe me…I support the ‘stroke call’ being put out, the team being assembled, the rapidity of radiological diagnosis, the attendance of the neurology team -- these are all factors which emphasise the importance of this neurological crisis…we just want the best possible treatment options with the best possible outcomes.

      Measured commentary and discussion with minimal bias are essential to define the best management algorithms and improve medical outcomes.

    • says

      With respect to Dr Franklin, you should perhaps recognise that some may find your comment about “generalists” somewhat insulting. Emergency physicians are clearly specialists in undifferentiated patients, which is subtly different. As such we have every right and indeed obligation to assess and analyse the evidence for any urgent/emergency condition we may encounter. We respect the expertise of neurologists as we do that of many other specialties, but surely you would concede that to blindly follow the “instructions” of other specialists without questioning and challenging to some degree would be an abandonment of our responsibilities to patients. We should ALWAYS be questioning the dogma of ourselves and others.

  10. says

    Then what are we doing?
    We are forever in a spiral looking for the hospital with a “Stroke Trial”.
    Ambulance crews don’t decide where treatment is efficacious, they chase stroke trials.

    Being met my teams in a higher degree of enthusiasm than PCI teams is attractive.
    Seeing, however their sadness and despair of a bleed on CT is terrible.

    Are we ever going to arrive at an ED that just initiates treatment or are we like CBD building works; someone is always building…..

    Sure if physical presentation warrants time critical intervention at scene or ED, then we go for it, but are we putting ourselves at risk moving with the speed of a thousand startled gazelles for treatment that doesn’t work?

    • Wombat says

      I dunno, Brent. I hear you RE Stroke trials -- they were the buzz at MMCC & Box Hill for awhile. But they’ve faded / ceased. BUT -- Over at MMCC where I take most of my stroke pt’s, if I notify the hospital about a pt I think may fit the criteria for thrombolysis, I am almost universally met within 10 mins of arrival by a stroke assessment team. Once they then ‘pull the trigger’ on rapid CT with view to treat a clot, I’ve seen some spectacularly good outcomes. And often in three-six hours post administration, not just after 24hrs.

      I guess what I’m concerned about, is are the outcomes in some of these trials being skewed by placing inappropriate patients in the trial? It’s recognised that there is always a trade-off for thrombolyitics -- we can’t just give these drugs to everybody having an occlusive stroke & expect them to do well -- but when administered to appropriate patients, they seem to work. Yes, it’s anecdotal, and I’m a firm believer in evidence-based care -- but surely the evidence should be used to support certain patient types being treated, not just to decide if we use the treatment at all?

      • says

        I’m not aware of any RCT that showed thrombolysis results in “spectacularly good outcomes” within 3 to 6 hours which is surprising if it really does happen “often”. Isn’t it just as plausible that you these were stroke mimics or TIA’s? (You know what would help sort this out? A good RCT!)

        With regard to the comment “surely the evidence should be used to support certain patient types being treated, not just to decide if we use the treatment at all”, isn’t that what David Newman and his minions are saying? ie do more trials and find out who benefits and who doesn’t. However, being old and cynical, I find it hard to believe that drug companies are going to fund trials that may result in decreased use of tPA

        • Wombat says

          As I said -- my comments are anecdotal. But I’m not talking about stroke mimics. Watching a patient with a diagnosed (on CT) clot have their symptoms resolve in a short time frame IS impressive. Yes, perhaps they would have without the tPA, but back in the ‘pre thrombolysis’ days, we never saw that sort of improvement on anything like a regular basis. So, if it’s not the throbolysis, what’s changed?

          • says

            I suppose I’d counter with: if you’re witnessing a real change, then why isn’t it reflected in clearly better outcomes for the treatment arms of the many RCTs?

            That’s no attack and it’s not even rhetorical, because I actually do believe (or at least find it plausible) that some patients benefit from tPA. In fact, I don’t think anybody disbelieves that; it’s not that the basic mechanism that’s contentious. Rather, the question is whether for every person who benefits (a small group, and we’re not sure who belongs in it), others are harmed, and those groups are clearly very similar in size. (Folks can get into the pit and argue over which is bigger, which they certainly do!)

            So pointing out dramatic improvements isn’t really a counter-example unless you also have observed a far SMALLER number of patients with harmful bleeds. If that’s the case, then you’re seeing something different than the majority of the studies have demonstrated. Maybe that’s because you’ve isolated the right subgroup for the drug, in which case, great! — publish it! But of course impressive anecdotal effects that disappear in large controlled trials are a very common phenomenon, and usually it’s because the big ol’ RCTs see things we don’t (and aren’t as prone to the same biases — in particular for this scenario, I suspect we’re more likely to recall the remarkable patients who come back from the abyss than we are the rather commonplace sight of a stroke patient getting worse).

            I am curious though (and I’m sure there’s literature on this) as to whether stroke outcomes have improved over the past couple decades; but if so it would be easy to ascribe most of this to other supportive care, particularly rehab.

  11. Michelle Johnston says

    I would like to thank everybody for the involvement in the discussion around this topic. If I could make a few further comments – this debate has arisen because there is not clarity about the results and the interpretation of the evidence to date. As has been repeatedly stated during these discussions, those with wariness about the conclusions to date have consistently stated that it appears that tPA will definitely benefit some strokes, but based on the totality of evidence thus far, it is not clear who this is, and that tPA will definitely harm some patients. We have no doubt that the highly respected neurologists and stroke physicians are refining this all the time, as evidenced by the comments and the research currently underway.

    Like Dr Cadogan. I work closely with our neurology team at my institution, and support in every way the coordinated rapid assessment and management plans by the stroke team, lead by very capable neurologists. This debate is not about preventing care, but understanding the limitations of the current state of evidence.

    It is hard to disagree with the vast anecdotal and inspiring evidence of stroke patients getting better in front of the eyes of the thrombolysing team, although it is important to note that, in every study, this happens equally with placebo as well as tPA.

    I would also not agree that non-specialty areas should not delve into the evidence that is not their area. Thank you for that point, Dr Carley.

    There is no argument that we want the very best for our patients. It would also be mush easier, and less painful to not be involved in this discussion. We are not the equivalent of climate change skeptics.

    When the evidence is unequivocal that we are choosing the most beneficial treatment, for the right patients, then this debate will be left long behind in a dusty corner. As stated in my previous post, Schroedinger’s Cat, we expect that with advanced imaging, drugs and techniques, it will not be long before that question will be answered, by the ground-breaking and trail-blazing researchers and clinicians for whom I have the highest respect.

    And, as a final, (I promise) to those that have questioned my right to post, I would like to say that the layman’s post was written by Prof Daniel Fatovich and the critical care post preceding by Prof Simon Brown, both highly respected researchers and academics. I have edited and supported.

    Thank you.

  12. Stephen Macdonald says

    In response to Dr Franklin’s comments, the single organ (or single disease) specialist may well have a detailed knowledge of a small subject area and rightly will advocate strongly for their patients. Stroke physicians see the devastating effects of this disease on a longterm basis. Emergency medicine specialists however have a unique perspective on the competing demands on finite healthcare resources and are in fact well qualified to weigh the relative merits of different treatments for their patients. Both groups genuinely want to achieve the best outcomes for the patients under their care.
    In acute stroke the picture is simply not clear with regard to the benefits of t-PA. While some may benefit we also know that some are harmed. Unlike MI where we have an objective bedside test to identify those in whom benefit outweighs risk this is not the case for stroke.The natural history is more complex than for MI. While everyone has an anecdote of a patient who has a miraculous recovery of their stroke symptoms shortly after t-PA administration, this also happens with no intervention. Moreover in none of the major stroke trials was there any difference in early functional status, with only purported benefit seen at 1-6 months follow up. There is a definite increase in symptomatic ICH and early mortality with t-PA in stroke although overall it appears neutral for death. Whether this is offset by a genuine reduction in disability however is unclear on the basis of current evidence for the reasons well described in the posts above.
    Rather than trying to discredit those who disagree with them, it is time the proponents of this therapy engaged genuinely on the science and tried to resolve these outstanding questions in the interests of patients, their families and the wider community.

  13. Prof John S Fennell says

    Most interesting topic: do thrombolytics really work for treatment of acute non-haemorrhagic stroke???? Just 3 days ago I was giving lecture on the issue, and warned the students to give the conventional answer for exam purposes, but to understand that I had misgivings about the actual benefits as portrayed in the medical media/ literature. I use the term ” the tyranny of the trials” to explain the situation. This is not my term, but fully agree. A consensus forms that something “works” and we are then caught up in the Tsunami that follows. If we don’t follow we are considered out of date, and may even end up being sued! You must become a “believer” However, in medicine you should hold a degree of skepticism, until there are multiple trials converging on 1 irrefutable conclusion. Many years ago, if I recall correctly, a drug known as Alredase(or something very similar by name) was widely used for treatment of peripheral neuropathy in diabetic patients. i myself just treated a handful of the worst affected patients. However, in due course the drug was withdrawn, as it was ultimately proven to be ineffective. The point of this story is that the diabetic community of physicians(diabetologists) had themselves not noted that it was ineffective, despite treating many, many patients. Thus, on a personal level it can be impossible to know if a particular drug is or is not working/benefiting your individual patient. Thus we are thrown back on the results of major double blind controlled trials, ete, to help us reach a conclusion. There are obviously many excellent, rigorously controlled trials carried out, but some are at the behest of the pharmaceutical industry, and must be interpreted with caution. They would never have been carried out without financial support, and no doubt the industry is hoping for a positive result, a potential source of bias, conscious or unconscious. Medical research itself is almost an industry, and like all industries needs to be regulated. I pose a question: is a trial with a positive result more likely to be published versus a trial with a negative result?? Prof JSF

  14. g lammert says

    P values …

    Certain fibrinolytics do have solid p values for select groups of ischemic patients.

    The study with TNKase vice TPA was was small, but elegantly designed with unchanged reasonable outcome endpoints.

    The p values instruct that chance was a high probability unlikely cause.

    http://www.nejm.org/doi/full/10.1056/NEJMoa1109842

    Look forward to the day when to use TPA vice TNKase is out right condemned … scientifically….

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