"A Timely Reexamination of the Case of the Thirteen Watches"

-Doing the same thing over and over again and expecting different results

Albert Einstein on Insanity-

For a near decade now our mad dash to the cath lab has been based off flawed data and an illogical certainty that every moment of delay is detrimental to our patients. As such we were completely flabbergasted when Menees et al published their findings in the NEJM in September 2013 (1). Despite reducing door-to-balloon time from a mean of 82 minutes to 67 minutes, no benefit in mortality was demonstrated. After 4 years and just over 95,000 patients, the authors were unable to demonstrate a benefit associated with this dramatic decrease in time to revascularization. These findings should not be as surprising as they initially appear. In fact, there is a multitude of evidence demonstrating that “time is myocardium” is a far more complex phenomenon than Door-to-Balloon time can account for. Rather than taking a rational data-driven approach to this pathology, we instead focused on the data that suited our desire to act. The evidence used to support our current STEMI guidelines is primarily based off an observation cohort published in JAMA in 2000 (2). This article by Cannon et al demonstrated a correlation between increased Door-to-Balloon times and increased mortality. The obvious shortcomings of these types of data sets and the mountain of evidence demonstrating the far more complex reality of time is myocardium can be found in a former post. What is important is how we utilized this limited data to serve our purposes and ignored the remainder of the evidence. With our blinders firmly attached, we chose to make door-to-balloon time the metric of choice when assessing quality in STEMI management.

Though the Menees cohort has reminded us that Door-to-Balloon time is very rarely an important metric, it is unlikely these findings will have any influence in changing our current practice. The momentum we have gained in this sprint towards futility has created a body with an inertial vector that is almost impossible to deflect. What this article should provide is a warning. An example of what happens when a healthcare system mobilizes extraordinary quantities of resources based off flawed surrogate outcomes. Currently we stand at a similar crossroads in yet another field of medicine. We are once again at the precipice of mobilizing these very same resources based on similarly flawed data. This time, the question at hand, is time brain?

In February of 2013 the results of 3 RCTs were published in the NEJM (3,4,5). They accounted for the largest and highest quality trials examining the efficacy of endovascular interventions for acute ischemic stroke. All 3 trials were universally negative. Though each trial had its own unique design, they were unable to demonstrate even trends towards benefit when comparing endovascular interventions to IV tPA therapy alone. So much so that the authors of the largest of the trials, IMS-3, state in their conclusion that these therapies should not be utilized outside the purview of a randomized control trial. Yet despite these universally negative findings, there has been a great deal of pressure to once again create the infrastructure necessary to deliver eligible patients swiftly to endovascular capable facilities. After all, every minute counts…

Time is brain has been a commonly accepted mantra of stroke management since the earliest inception of reperfusion therapies. And much like the overall efficacy of reperfusion therapy in acute CVA, the data addressing the time is brain hypothesis have yielded mixed results. In the area of thrombolytic therapy the largest, highest quality data sets have failed to uncover any convincing evidence that time to treatment is an important determinant of neurologic outcomes. The Cochrane Database examined all 26 trials comparing thrombolytics to placebo and found no evidence that time-to-treatment affected outcomes (6). IST-3, the largest trial to date examining thrombolytics in acute ischemic stroke found no temporal relationship between improved outcome and time-to-treatment (7). Finally the NINDS trial, the rallying cry for tPA apologists world-wide, in its original manuscript the authors were unable to demonstrate that patients who received the tPA in under 90 minutes fared better than those treated in the 90-180 minute window (8). In fact, when Dr. Jerry Hoffman and Dr. David Schriger reexamined the patient level data from the NINDS cohort, they too found that time to treatment had no association with 3-month neurological outcomes (9). Moreover when they accounted for the obvious baseline differences present in the NINDS trial (10) (using change in NIHSS at 3-months) the overall benefit of tPA also disappeared.

Other than a highly selected review of eight cherry picked trials published in the Lancet in 2010(11), no analysis of RCT data has demonstrated a temporal benefit to IV tPA therapy in acute ischemic CVA. A number of publications using registry data have attempted to examine the time is brain phenomenon. Two such studies were published a month apart from one another in JAMA and JAMA Neurology (12, 13). These trials used similar registries, similar methods, and similar statistical analysis and yet found completely antipodal results. These contradictory findings are less of a comment on the truth of the temporal relationship of revascularization than on the limitations of such data and how it will submit to even the smallest amount of statistical coercion. In a brilliantly written letter to editor by Dr. Ryan Radecki addresses the flaws in the conclusions drawn by Saver et al, authors of the JAMA article that concluded time is in fact brain (14). Dr. Radecki writes:

Dr. Saver and colleagues used the Get With The Guidelines–Stroke (GWTG-Stroke) registry to investigate the association of time to tissue-type plasminogen activator (tPA) treatment and outcomes from stroke. However, the authors did not address the handling of transient ischemic attacks (TIAs) and stroke mimics within the registry, which is a potential confounder in the abstraction method used in the study.

Most recently the authors of IMS-3 published a secondary analysis of their cohort in an effort to demonstrate that similar to IV tPA therapy, with endovascular treatments, time to reperfusion matters (15). Using the IMS-3 cohort, these authors examined the association of time to endovascular intervention and 3-month functional neurological outcomes. After retrospectively excluding patients found not to have large vessel occlusions (the proximal MCA or ICA terminus), Khatri et al found a statistically significant association with time-to-intervention and improved functional neurological outcomes. Like the Cannon and Saver cohorts, this data is severely flawed. There are a multitude of reasons why patients may be delayed in receiving endovascular therapy. Most obviously they were sicker and required some form of stabilization before being transported to the intervention suite. In fact after the authors account for some of these confounders by utilizing multifactorial logistic regression, the overall effect that time to intervention had on functional neurological outcomes translated to a coefficient of determination (R² ) of 0.18. Meaning that 18% of the variation in neurological outcomes at 3-months can be explained by time-to-intervention. The remaining 82% is determined by other factors. Clinically a very small effect. Especially when considering this regression model did not account for the fact that the subgroup of patients treated in a more timely fashion were far more likely to include patients having a TIA or a stroke mimic, who will universally have a better outcome independent of the intervention they receive. More importantly this was a negative study which found no difference in 3-month outcomes between patients who received IV thrombolytics plus endovascular treatment or IV thrombolytics alone.

This is observational data demonstrating a small association with time to treatment and improved outcomes. Using this data the most we can say is, patients who take longer to receive a therapeutic intervention have worse neurological status at 3-months. The corollary statement, reducing this time to treatment will improve neurological outcomes, cannot be made and taking into account the summation of the data on reperfusion therapies for acute ischemic stroke, is most likely false.

Data sets like the Cannon and Saver articles should not be mistaken as investigations in search of scientific truths designed to answer clinically relevant questions. Rather these publications are examples of how easily we can manipulate data to serve our purposes. Like its predecessors the Khatri et al reanalysis of the IMS-3 cohort appears promising as long as you choose to ignore the control group. At this point all we have to support the efficacy of endovascular therapies in acute ischemic stroke are stories of patients rising from the cath lab table reciting poetry they never knew before their infarct and perfusion studies taken after the intervention showing near normal restoration of blood flow. Let us note confuse anecdote and pretty pictures as evidence of benefit. Using such data to justify the restructuring of our healthcare infrastructure is unwise. The resources required to train an army of interventionists to be ready at a moments notice, equip a nation of cath labs to be accessible 24 hours a day, and mobilize a pre-hospital system to deliver these patients swiftly and safely to the facilities capable of endovascular interventions would be massive. All for a treatment that not only has failed to demonstrate efficacy over our current “standard of care”, but for a theory of temporal urgency that has never been demonstrated in a conclusive fashion. It is not hard to imagine that if we fail to heed the warnings of the Menees trial, in 13 years the NEJM will once again publish findings from a large national registry. Only on this occasion it will be examining patients undergoing endovascular interventions for acute ischemic stroke. Like the Menees cohort this registry will demonstrate that over a 5-year period we have reduced time to intervention impressively. And yet despite this effort and the massive resources invested to achieve it, this cohort failed to demonstrate any improvement in neurological outcomes. We will be left wondering where we went wrong.

Here and now…

Sources Cited:

1. Menees DS et al. Door-to-balloon time and mortality among patients undergoing primary PCI. N Engl J Med. 2013 Sep 5;369(10):901-9

2. Cannon CP, Gibson CM, Lambrew CT, et al. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA. 2000; 283: 2941–2947.

3. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903

4. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368:904-913

5. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-923

6. Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD000213.

7. The IST-3 collaborative group. 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 2012; 379

8. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587

9. Hoffman JR, Schriger DL. A graphic reanalysis of the NINDS Trial. Ann Emerg Med. 2009 Sep;54(3):329-36, 336.e1-35.

10. Mann, J. Efficacy of Tissue Plasminogen Activator (Tpa) for Stroke Truths about the NINDS study: setting the record straight. West J Med. May 2002; 176(3): 192–194.

11. Lees KR, Bluhmki E, von Kummer R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet. 2010 May 15; 375(9727): 1695-703.

12. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA. 2013 Jun 19; 309(23): 2480-8.

13. Ahmed N et al. Results of Intravenous Thrombolysis Within 4.5 to 6 Hours and Updated Results Within 3 to 4.5 Hours of Onset of Acute Ischemic Stroke Recorded in the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR): An Observational Study. JAMA Neurol. 2013;70(7):837-844.

14. Radecki RP. Acute ischemic stroke and timing of treatment. JAMA. 2013 Nov 6;310(17):1855-6

15. Khatri et al. Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial. The Lancet Neurology – 28 April 2014