Thrombolytic Use in Ischemic Stroke


Brain CTUse of thrombolytic therapy in ischemic stroke is a perennial hot topic. Chances are that you will have as many people swearing AT the idea as you have swearing BY the idea of using thrombolytics for acute strokes. That fact alone should demonstrate that there is no “standard of care” for thrombolytic use in ischemic strokes.
If reasonable board certified doctors can’t agree that the risk of tPA outweighs the benefit of using tPA, how can there be a “standard” for using it?

I could go through the data and discuss the pros and cons of each trial studying thrombolytic use, but Dr. David Newman has done a far better job than I could ever hope to do and his analysis of thrombolytic therapy in acute ischemic stroke is published on In summary, of the available studies on thrombolytics up to March 2013, Dr. Newman found …
Two studies showed a marginal benefit in using thrombolytics
Four studies showed a demonstrable harm in using thrombolytics
Six studies showed no benefit from using thrombolytics

Back in 2011, EP Monthly asked for opinions on thrombolytic use for acute ischemic stroke in its now-defunct Standard of Care project, but those important data were never published or made available to the people who voted.

The debate over tPA use came to a head last year when ACEP representatives met with experts in the field of ischemic stroke, including representatives from ACEP and AAN and developed a policy which was then reviewed by representatives from the Society for Academic Emergency Medicine, the Emergency Nurses Association, the American College of Physicians, the Neurocritical Care Society, the American Academy of Family Physicians, the National Stroke Association, and the American Stroke Association.
The final “evidence based” policy advocated “offering” tPA to acute ischemic stroke when certain criteria were met (.pdf file).  This recommendation was given a “Level A” status, meaning that it constituted

Generally accepted principles for patient management that reflect a high degree of clinical certainty (ie, based on strength of evidence Class I or overwhelming evidence from strength of evidence Class II studies that directly address all of the issues).

Needless to say, there was a lot of discussion after these “evidence based” “guidelines” were published.

Some people questioned whether this “evidence based” policy would create worse patient outcomes. Others were concerned that the guidelines, even though they contained a disclaimer, could create legal liability when not followed. Still others wondered whether this clinical policy was even helpful in determining a course of action since there was no “consensus” statement, only an “evidence based” policy.

Then the British Medical Journal advocated using a healthy “skepticism” in reviewing the data since almost all of the study authors had either direct or indirect ties to companies that manufactured thrombolytics:

for one of the guidelines recommending alteplase, seven of eight panel members had ties with industry: three had direct relationships with companies that market alteplase, while four had links with an educational foundation wholly funded by industry, whose president and founder was an outspoken advocate for alteplase on acute stroke. The remaining author had resigned from the panel six years earlier

Even more troubling is that several of those authors allegedly did not disclose their ties to the manufacturers in the publication of the clinical guidelines (which, if true, would constitute an ethical violation). See table below – taken from this article.

Thrombolytic Author Conflicts of Interest and Disclosures

EM Literature of Note Blog weighed in on the issue, stating:

Whichever side of the expand/limit tPA in acute stroke debate you fall upon, the issues of sponsorship bias, one-sided panelists on a still-controversial practice, and lack of open peer review for the ACEP/AAN guidelines ought to be unacceptable.

Ten months later, ACEP just might be listening to some of the criticism. There is now a form on the ACEP web site where, for the next 60 days, ACEP members can comment on the thrombolytics in acute stroke policy and provide “supporting evidence” for their comments. These comments will then reportedly be presented to the ACEP Board.

I encourage interested parties to go to the site and add their comments.

Unfortunately, we don’t know whether the comments will also be available for public view. That’s the reason for this post.

I’m asking two favors from the readers who have an opinion on this topic.

First, vote in the poll below. It will provide data that will hopefully be available for web searches far into the future.
Second, if you have an opinion or additional “justification” that you plan to enter on the ACEP site, please also enter it into the comment section below. In that way, the comments – both pro and con – will be available for public review and discussion.

When answering the poll, keep in mind that the “standard of care” is what a reasonable physician would do under the same or similar circumstances. As noted on the defunct Standard of Care site, the standard of care is NOT “what the Best Practice would be, (arguably the top 5%); or what YOU would do (the top 25%); or or even what MOST physicians would do (the top 50%).”

The standard of care is the tipping point between “negligent” and “non-negligent” behavior. In essence, the question as asking whether a doctor has violated the standard of care and is therefore negligent and liable for damages if he or she does not administer tPA to an acute ischemic stroke victim.

[poll id=”12″]

Please don’t forget to add comments in the comment section!


  1. Pingback: An overview of the “tPA for stroke” debate – and an opportunity to vote | The ACUTE CARE Blog: Non-Urban Emergency Medicine

  2. I think this subject needs more evidences before becoming an unquestionable strong recomendation; the NNT analysis showed only marginal or not benefits and some harms. A large scale study -like the one done on corticosteroids in acute traumatic brain injury(CRASH)- should be done

  3. Arthur Freeland on

    Ever since the NINDS trial, my conversation with patient includes three main facts: There is a significant chance their stroke related symptoms will improve significantly without thrombolysis; There is a modest but significant likelihood that they will be more functional down the road if we do use the thrombolytic; and there is a smaller but very real possibility that the treatment will worsen their condition dramatically or even kill them. The patients that would rather die than have dramatic disability see the tradeoff immediately and go for it. The remainder we can talk actual numbers – and as I recall the number needed to harm is less than twice the number needed to treat.

  4. Remember 10 years ago when everybody was getting activated protein c for sepsis? Now nobody does. Eventually shown to be ineffective .

    Wouldn’t be surprised of tPA for acute stroke has the same fate.

  5. It is a persons choice, but the person can’t express their wishes.
    The studies of benefit vs harm can be skewed by the authors definitions of a good outcome.
    Myself, I would take tPA, because I would not want to live half paralyzed , but I don’t think this is in the benefit vs harm. Death is always a “bad” result.

  6. The vote is screwy. The same statement is in twice.
    I think doctors should NOT be liable for malpractice if they do not give thrombolytics to an ischemic stroke patient who meets standard inclusion criteria

    I think doctors should NOT be liable for malpractice if they do not give thrombolytics to an ischemic stroke patient who meets standard inclusion criteria

    • I will have to get a screen shot of the vote statements from a “virgin” computer, because the original page can not be returned to with “cookies” or IP tracking enabled.

    • You cut out the beginning of the questions that you quoted.
      There are six choices – three each “liable” or “not liable” choice which are divided into physicians, non-physician medical providers, and those not in the medical field.

  7. On a Monday afternoon, in June of 2006, my elderly father had a stroke. By Thursday morning he was dead.

    The week previously, he had had a Moh’s {spelling} procedure (at a Dermatologist’s clinic) for squamous cell skin cancer on his face. (He was due to get his sutures removed the day after his stroke.) Dad was taken off of Coumadin the week before the procedure, and had not yet been told when he could restart it.

    Dad was taken to the hospital (two short blocks away) by ambulance. He was given a very brief and cursory exam, then left in the corner of an equipment storage room until the window for using a clot-buster drug was past.

    If Dad had received a clot-buster drug when he first arrived at the hospital, then he probably would still be alive. All that was done for him was very meager palliative care, not even a feeding tube.

    • Sorry for the loss of your father but your lat paragraph is quite debateable.

      He MIGHT have lived if given the clot buster. He MIGHT have had severe disability. He MIGHT have added a brain bleed on top of his stroke and died right there in the ER. He MIGHT not have met criteria for TPA for a variety of reasons.

      There is no ‘PROBABLY’ about any of these other than the last sentence. That is the only one that could be reviewed and be potentially knowable.

    • So, besides suing the dermatologist, the ER doctor, and the hospital he was taken to are you going after anyone else? Do you really expect us to believe that a patient with stroke like symptoms taken to an emergency department by ambulance was left in the corner of an equipment storage room?

      • The dermatologist was in a town 132 miles away.

        The hospital is the only one in our 10,000+ square mile rural county, with a population slightly less than 10,000. At the time the only doctor there was a Family Practice doctor, from the clinic next door.

        The storage room was so full of equipment that there was no place for Mom or me to sit down, so we stood by Dad’s gurney while we waited. After the window for using a clot-buster was past Dad was taken from the equipment storage room to a trailer outside to get a CT scan. Then he was admitted to a room.

  8. As I recall, 85% of strokes are ischemic and the rest hemorrhagic. Is imaging routinely done to determine the type of stroke. Naturally, one wouldn’t use thrombolytics in hemorrhagic stroke, but might benefit if ischemic and within the magical 3 hours. What if pt is unresponsive and no family is there to discuss risk/benefit of thrombolytics? Is that even an option to consider or potential career suicide?

    • >Is imaging routinely done to determine the type of
      >stroke. Naturally, one wouldn’t use thrombolytics
      >in hemorrhagic stroke, but might benefit if
      >ischemic and within the magical 3 hours.

      Yes. One of the first things that happens to an ambulance arrival for stroke like symptoms (other than possibly getting an EKG and bedside blood glucose measurement) is that they are transported off to the CT scanner for a noncontrast CT scan of the brain.

      >What if pt is unresponsive and no family is
      >there to discuss risk/benefit of thrombolytics?
      >Is that even an option to consider or potential
      >career suicide?

      In many of these cases there is no “last seen normal” time that would place the onset of symptoms within the window for administration. In most cases where TPA is a possibility, the stroke patient was either with family that observed the onset of symptoms, or was on the phone with them and heard something change…or perhaps talked to them on the phone and then went to their house shortly thereafter.

      In most cases of stroke, the patient either seems to wake up with the symptoms or family or nursing home staff can only verify that they were last seen normal in the morning the day of (hours outside the window), or the previous night.

  9. This will be an issue that ED physicians will not win. Neurologists all over the country have drunk the tPA Koolaid, as have EMS squads, hospital administrators, and of course Big Pharma. Second generation reperfusion studies that are based on MRI results are in the works, based on the assumption that IV tPA “works”. I give tPA to eligible stroke patients only because I am likely to be sued if I don’t, not because I believe it is the best treatment for these patients. This makes me feel very conflicted and uncomfortable.

    • Long Time E.D. Doc on

      The very reason big pharma went after neurologists along hospital administrators, EMS, State Legislators (think “Stroke Centers”)was exactly because the E.D. physicians looked at the data closely and remained skeptical. We did not swallow the findings of big pharma whole and accept it as defacto standard of care. A huge thanks to Jerry Hoffman, among many, for his words of wisdom are definitely in order.

      I am guessing more data will come to light showing the lack of clear benefit relative to the risks right around the time tPA becomes generic.

    • Hopefully this post and the feedback that ACEP gets will change the game – even if just a little.
      So far, more than 90% of people voting (including 134 physicians) believe that there should be no liability for failing to give thrombolytics.

      Based on faulty evidence by investigators who have ties to the thrombolytic manufacturers when many studies show a harm in giving thrombolytics, almost all the other studies show no benefit, and now a 10% minority advocating its use, we’re going to say that thrombolytic administration is the “standard of care”?

      That’s a pretty difficult argument to make – at least with a straight face.

      Any expert testifying that administering thrombolytics to an acute ischemic stroke patient is the “standard of care” without disclosing the results of ALL the studies on the topic should be brought up on ethics charges and have a complaint filed against him or her with the state licensing board.
      Any defense attorney who doesn’t cross examine the experts about every one of these studies when defending a “failure to administer thrombolytics” case is committing legal malpractice.

    • Not all of EMS has “drunk the tPA Koolaid”. I think instead we’ve drunk the Comprehensive Regional Stroke Care System Koolaid, after seeing our large gains in STEMI and Post-ROSC care. Rapid activation of a system of care for our stroke patients probably has a much higher effect size than tPA does given the available evidence.

      It is pretty rare actually that one of our Code Stroke patients gets tPA, reviewing our feedback forms.

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  13. I am a “consumer”, and I’ve always felt tPA was a bad deal, but after reading the summaries of the 12 available trials on TheNNT, I’ll be discussing this issue with my husband and elderly parents to make darn sure neither of the latter – or potentially myself – is ever subjected to this treatment.

  14. None of us who have practiced long enough come to these tough discussions without dirty linen and skeletons in our own closet.
    At one time when our group was doing wound care and hyperbarics I certainly thought just about everyone with a wound or a CO exposure needed to dive.
    When the pro fee for diving patients was markedly adjusted many of my patients, I found, could heal their wounds quite well without hyperbaric treatments. And those pesky Australians and their darn studies on CO patients certainly changed our approach from everybody to an occasional somebody.
    What is true is that we all find justification for our treatments.
    What is also true is that it is darn hard to do good science.
    Whether TPA works for strokes is not as easy as it was for MI’s.
    Anyone who saw perfusion restored after administering TPA in an anterior wall MI and our patient go from heading to the morgue to the golf course would say that TPA works for the myocardium.
    And we had a bunch of 20,000 case studies to confirm what our eyes were telling us.
    My understanding is that endogenous TPA in the heart is present in huge amounts making it easy to sprinkle a little into the patient to open up a coronary artery.
    Endogenous TPA in the brain is as hard to find as an ED doc who thinks patient satisfaction scores are not an appendix to Alice in Wonderland.
    So we have to dump in a lot more into the brain to bust a clot. Nearly as much as is needed to create spontaneous cerebral hemorrhage.
    The whole subject of TPA for strokes needs a big enough N to say yea or nay.
    While we do that study we need to give the patient and family the truth- which is that we do not know for sure if TPA works well enough in strokes to offset the complications from using it.
    While we wait for the numbers we can only continue to do our best in difficult circumstances and with nearly impossible time constraints and get down in front of them, hold their hands, look them in the eye, and tell them the truth as best we know it.

  15. Medical providers should be liable if they do not offer TPA to patients when concerned for acute ischemic stroke and meet the inclusion criteria for lytics.


    Chart: Discussed potential risks, benefits and alternatives to tPA. questions answered. patient elected to receive tPA / declined tPA.

  16. Oh yeah; let’s not follow AHA/ASA guidelines on the one hand (tPA), but follow them on the other (ACLS, etc.). We need to remember and realize where these research papers come from and be equally skeptical of them as we are of Big Pharma, etc. Is ACEP seriously going to NOT recommend tPA when we’ve been using it for the past 20 years with at least some evidence that it works? We really need to step back and take a look at what’s being talked about here with this “vote.”

    “Gentleman! There’s no fighting in the war room!” – Dr. Strangelove

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