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?
Why after 23 years do we still not know the answer?
- 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 Trialâ€“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 Trialâ€“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: 811â€“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.