On March 26th 2018, the New York Times published an article by Gina Kolata, For Many Strokes, There's an Effective Treatment. Why Aren't Some Doctors Offering It?, examining the efficacy of tPA in acute ischemic stroke. The article was dismissive and misleading. In response, I sent a letter to the editor which I fear will never see the light of day. What follows are my thoughts in their expanded form without the constraints of the 175 word limit imposed by the editors of NYT.
In November 1995 stroke care as we know it drastically and permanently changed. With the publication of NINDS-2, the NEJM ushered in the interventional era of acute ischemic stroke (1). No longer were we powerless in our management of these patients. Finally we could offer them more than an aspirin to chew on, a corner to sit in, and a consultation with a neurologist in the morning. And yet, NINDS-2 was not the first trial examining thrombolytic therapy for acute ischemic stroke. In fact three trials were published prior to NINDS-2, all of which were negative (NINDS-1, MAST-I, ECASS-1), with two finding an increase in mortality for patients given thromblytics (1,2,3). With the publication of NINDS-2 this was forgotten. NINDS-2 was impressively positive, demonstrating a 13% absolute increase in patients who were given tPA that were alive and independent (mRS of 0 or 1) at 90 days (1). Supporters justified the 6% absolute increase in symptomatic intracranial hemorrhage by arguing that it did not increase 90-day mortality (21% vs 17%).
Despite these impressive results there were still three negative trials to account for. What made NINDS-2 different than all the trials that came before it? Was it the agent? Supporters claim that tPA is the superior thrombolytic and we should ignore all trials studying other agents. Was it time? NINDS examined patients who received tPA within 180 minutes of symptom onset (half in under 90 minutes); two of the earlier trials examined patients who received thrombolytic therapy over a much broader treatment window. Was it the patient population? The authors of NINDS used very strict selection criteria to determine which patients were acceptable candidates. There was of course a fourth reason proposed by a less enthusiastic contingent, that being random chance. This more skeptical party posited that an intervention that possesses little or no efficacy, if studied enough times would eventually demonstrate positive results simply by chance alone. They reminded the more eager supporters of tPA therapy that though the findings of NINDS-2 may be true, taking these results at face value without further validation was not only bad science, but even worse medicine. Despite these warnings, the FDA fast tracked the approval of tPA for acute ischemic stroke in under 3-hours and all other trials attempting to validate this benefit were abandoned.
Six consecutive trials were published following NINDS (all examining time windows greater than 3 hours). All six were negative and four demonstrated harm (4,5,6,7,8.9). It was not until the 2008 publication of ECASS-3 that another trial examining thrombolytics for ischemic stroke demonstrated benefit (10). These benefits, though not as impressive as NINDS-2, were convincing enough to make us forget the multitude of negative trials examining similar time windows. Unlike NINDS-2 we were unable to claim ECASS-3 was different than these other negative trials examining similar patients during similar time windows. So instead, we just ignored them.
Since then meta-analyses have been performed, guidelines have been written and financially incentivized performance measures created. And while each of these add some authoritative legitimacy, none can circumvent the fact that the science is incomplete. No matter how small a p-value you tag on to a meaningless effect size, how many industry sponsored names you add to a level 1A recommendation, or how big a financial incentive you attach to the administration of tPA, it does not replace a high quality trial validating the findings from the original NINDS trial.
Gina Kolata's article failed in many senses. It failed because it misrepresented the data examining thrombolytics in acute CVA. It failed because it misrepresented the debate surrounding this literature. Her depiction of those that question the evidence supporting the use of tPA, paints expert clinicians and methodologists as merely uninformed charismatic bloggers. But most importantly, Ms. Kolata's article failed because it did not identify the core argument at the center of the debate regarding tPA for the treatment of acute ischemic stroke.
Why in the intervening 23 years since the publication of the NINDS trial do we continue to exist in a state of evidentiary uncertainty? The fundamental underpinning of scientific inquiry is the ability to reproduce ones results. In light of this, why have we ignored one of the most basic tenets of our scientific method and not validated NINDS findings? The answer is simple, from a monetary standpoint, a second positive trial offers nothing. But a negative trial disproving the first, would invalidate its findings, and harm those that stand to gain financially from the wide unrestricted use of tPA.
As Elliot Grosbard, Genentech scientist, stated in internal communications regarding further trials comparing streptokinase to tPA for acute coronary syndrome;
We don't know how another trial would turn out. And if we don't come out ahead, we would have a tremendously self-inflicted wound . . . [another study] may be a good thing for America, but it wasn't going to be a good thing for us. (11).
Such methodologically negligent practices are not isolated to the use of tPA in acute ischemic stroke, but rather are rampant throughout modern medical science. They are the natural consequence of a society that values profit over scientific truth. The larger issue of science in medicine is a far more difficult conversation to have, so instead we discuss p-values, NNT, and other methodological quandaries.
The question should not be,
Is tPA effective for the treatment of acute CVA?
But rather,
Why after 23 years do we still not know the answer?
Sources Cited:
- Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-7.
- Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. Lancet. 1995;346(8989):1509-14.
- Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017-25.
- Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial–Europe Study Group. N Engl J Med. 1996;335(3):145-50.
- Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996;276(12):961-6.
- Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352(9136):1245-51.
- Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282(21):2019-26.
- Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study: Thrombolytic Therapy in Acute Ischemic Stroke Study investigators. Stroke. 2000; 31: 811–816.
- Hacke W, Furlan AJ, Al-rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8(2):141-50.
- Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-29.
- Lenzer J. Alteplase for stroke: money and optimistic claims buttress the “brain attack” campaign. BMJ. 2002;324(7339):723-9.
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The author either does not know about the basic principles of evidence-based medicine, or he refuses to apply them. The meta-analyses clearly have shown a positive effect of rt-PA in acute ischemic stroke within the first 3 hours and also in the first 4,5 hours (Emberson et al, Lancet 2014). Because of that, there is no need for further studies. No ethics committee would approve another placebo-controlled study of rt-PA within 3 hours, as there is already Level 1A-evidence. This discussion should have long been over and it is frustrating for me as a stroke neurologist to still read well-written,… Read more »
Thanks for your response Simon. I think we will have to agree to disagree, both on your overall conclusion of the data and my understanding of it. First the meta-analysis you cite is one of many. Specifically the Emberson et al analysis is irredeemably supported by industry. More balanced analysis performed by less conflicted authors have found far less enthusiastic results results (Wardlaw et al, Cochrane 2014, Donaldson et al, EMA 2016). Even still a meta-analysis of the current data does not replace a high quality RCT validating the findings of the original NINDS data set. Performing a meta-analysis of… Read more »
Hello Rory, first all of, I would like to apologize for the uncivil first paragraph. However, meta-analyses are the highest pillar of evidence and I do not see the issue of “flawed data” (what data is flawed and why?). Of course it is difficult to compare studies using different time windows and different fibrinolytics. But individual patient-data metaanalyses should be able to do exactly that (and even though the other two metaanalyses are less enthusiatic, all three clearly show better outcome with rt-PA). In addition to that, a number of registry studies have shown very good outcomes using rt-PA (and… Read more »
Really. How exactly, does it work, then? Stroke is a bad disease — I get it, 20% mortality in 30 days; we don’t work with too many conditions that are worse than that. Nevertheless, among the 700,00 annual stroke victims there are survivors: some are extremely debilitated and disabled and a rather large subset are completely normal and functional. I don’t find it a coincidence that those with a livelihood conflict-of-interest are so rabid about stroke fibrinolysis for this disease, especially in patients who are effectively universally funded. Restoring circulation to ischemic muscle is effective and makes physiologic sense. Restoring… Read more »
Hi Edward, aside from the discussion about biostatistics, I feel you have one or two of misconceptions about cerebral pathophysiology and rt-PA and I would like to help clarify those. First of all – I don’t have any conflicts of interest, aside from a inherent will to maximize good outcome in my stroke patients (which will, admittedly, draw be to favour possible interventions). I work in a system where all patients are insured, I don’t get any monetary advantages (or disadvantages) from using or not using certain drugs or interventions. By the way (as you were talking about a “multibillion… Read more »
I have studied this problem carefully for over 20 years and of this I am certain: there is a subset of stroke patients who may benefit from fibrinolysis; and, we cannot identify those patients. Unless there is some other role that tPA is playing it makes no physiologic sense. We are limited by no good gold standard for the diagnosis. I have seen, from the inception, this multibillion dollar industry. I have seen many patients harmed with Alteplase with symptomatic ICH plus all the trappings of suspected AIS that go along with the treatment, once the jeanie is let out… Read more »
Hello Edward, thank you for your insights, this is a very interesting discussion. In the country where I work, there are no emergency physicians (only in the prehospital setting), so as a neurologist, I treat all neurological emergencies in the ED myself. So my world is quite a bit different here and unfortunately, no robots ease my work. 🙂 However, I don’t quite understand the argument with rt-PA creating wrong stroke diagnoses – or additional healthcare costs. In my tertiary stroke center, a thrombolysis patient doesn’t get any additional care because of rt-PA (why should he?), all stroke patients (with… Read more »
Nice Post. Keep us updated
I sent a similar but not nearly as clear to the NYT Actually wanted to claim “fake news” but thought that would put me in a bad light with thinking people. Probably the biggest failure of our society is we have turned the pursuit of science into the pursuit of money in medicine. We reward the people who make a lot of money but not the people who produce good science (Nobel prizes aside). First patient I had after our neurologist drank the Kool Aid refused the TPA (sounded too risky to him) next morning was neurologically normal thats why… Read more »
Simon, thanks for your comments. There is one point I can’t explain. you write : ” In patients with smaller strokes,… But of course, you see the clinical effect of thrombolysis/recanalisation within minutes or hours (sometimes it takes critically underperfused cells a little while to regain function, but that is usually within the first hours). We see patients with minor strokes symptoms which are resolved within minutes of initiation of thrombolysis every day. The 90-day-windows are about the first follow-up and used in the studies, as there are way less confounders compared to a 1-day-outcome.” I’m not convinced that the… Read more »
Hi, this is definitely a very valid and important point. Quite a few stroke patients (not only TIAs) improve within the first few hours, this is believed to be at least in parts caused by spontaneous re-location of the thrombus (f.e. M1 -> M2, M2 -> M3, etc.) or sometimes even spontaneous recanalisation. Of course, this natural course of disease can be misinterpreted as a treatment effect and this is a issue in all stroke intervention studies. As you specifically mentioned NINDS 1 and 2: If you look at the NINDS 1 and 2 early (24h) NIHSS scores (direct link… Read more »
Veil of Science, Nice and informative post
The discussion on this post is excellent!
Maybe in Canada it is used more? 10 years ago in our small Collingwood Ontario EM room, I was given tPA and transferred to South Lake Hospital in Newmarket. Ontario. I did hear the nurses commenting on the fact that I had been given it, but didn’t know if that was good or bad. I was asked in Collingwood if I would like to try it and given the odds on a stroke happening if I allowed the use of it, and went for it anyways. As a patient, I often ask the Dr’s, if I was your wife, what… Read more »
Small update: The Wake-Up trial I spoke about earlier has just been published in the NEJM. In short summary, thrombolysis with rt-PA improved outcomes in stroke patients with unknown symptom onset and FLAIR-DWI mismatch. Of course, this does not really go into the basic questions discussed before, but still adds new information on selection of stroke patients beyond known system onset time.
https://www.nejm.org/doi/full/10.1056/NEJMoa1804355?query=featured_home
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