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Myths in Emergency Medicine: Time is Brain (Does It Matter if Therapy Can't Reperfuse?)

Spiegel, Rory, MD

doi: 10.1097/01.EEM.0000531125.78261.a1
Myths in Emergency Medicine

Dr. Spiegelis a clinical instructor in emergency medicine at the University of Maryland Medical Center. Visit his blog athttp://emnerd.com, follow him on Twitter @emnerd_, and read his past articles athttp://bit.ly/EMN-MythsinEM.

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It is a phrase universally accepted as truth since the early days of thrombolytic therapy: Time is brain. Yet, the evidence supporting this claim has been inconsistent at best. There does seem to be some temporal relationship between ischemic time and infarct size, but the linearity of this relationship is unclear.

The recently published “DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo,” or the DAWN Trial, presents persuasive evidence that empiric time-based cutoffs are inappropriate metrics for identifying patients who could potentially benefit from reperfusion therapy.

The researchers enrolled patients presenting to the ED with acute ischemic stroke between six and 24 hours after symptom onset, evidence of occlusion of the intracranial internal carotid artery, the first segment of the middle cerebral artery, or both on computed tomographic angiography or magnetic resonance angiography, and a mismatch between the severity of the clinical deficit and the infarct volume on neuroimaging. Patients were randomized to standard medical management alone or the addition of endovascular thrombectomy. (N Engl J Med 2018;378[1]:11.)

The authors randomized 206 patients presenting to 26 centers in the United States, Canada, Europe, and Australia from September 2014 through February 2017. The authors reported extraordinary success. Forty-nine percent of patients randomized to the thrombectomy arm achieved functional independence (mRS score of 0, 1, or 2) at 90 days compared with only 14 percent of the patients in the control arm. Forty-eight percent of the patients in the thrombectomy arm experienced a significant early improvement in symptoms (defined as a decrease of NIHSS of 10 points or greater or an absolute score of 0 or 1 at days 5, 6, or 7) compared with only 19 percent of the patients in the control group.

Reperfusion was achieved in 77 percent of the patients in the thrombectomy group with only 36 percent of the patients in the control group at 24 hours. Neurologic deterioration occurred in 14 percent of the patients in the thrombectomy group compared with 26 percent of the controls.

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Eccentricities

These results are fairly robust and likely represent a true utility of endovascular therapy in this subset of stroke patients, but this trial contains a number of eccentricities that may have influenced the findings. First, the authors' primary endpoint was the mean score for disability on the utility-weighted modified Rankin scale at 90 days. The authors attempted to attribute a weighted value to each mRS score. Essentially, the numerical mRS score is intended to represent the patient's underlying functional status. The mRS functions as an ordinal scale, but the integral distances between values are not equal. Shifting from a score of 2 to a score of 0 is not equivalent to shifting from a score of 6 to a score of 4.

The authors argue that a simple ordinal analysis that treats all shifts equally is not appropriate because of this. Rather, creating a weighted system based on patient- and clinician-centered judgments, which assigns a score to each mRS value, better represents the potential benefits of any therapeutic intervention. In this case, mRS scores of 0, 1, 2, 3, 4, 5, or 6 were assigned values of 10, 9.1, 7.6, 6.5, 3.3, 0, and 0. When taken on face value, this seems like a reasonable outcome measure. In reality, its implementation may be somewhat problematic.

Two clinicians assessing the same patient will often disagree by as much as 2 points on the mRS. These discrepancies are more prevalent in the intermediate scores (mRS values of 2, 3, 4), and patients with values on either end of the scale are evaluated more reliably. (Stroke 1988;19[5]:604; 2002;33[9]:2243; 2005;36[4]:777.) Even in a simple ordinal analysis, these inconsistencies can be problematic, but in a weighted analysis, these inconsistencies will be potentiated because each incremental error causes a shift in the weighted scale rather than just the simple mRS.

To imagine that an unblinded cohort, in whom approximately 25 percent were evaluated via a phone interview, possessed the granularity to perform such an analysis is difficult to believe. The most inviting motivation for such an analysis is the same reason trialists abandoned the traditional dichotomous outcome measure in favor of the standard ordinal analysis, increased statistical power.

The second issue, like the majority of trials examining the utility of endovascular therapy in CVA, is that the DAWN trial was stopped early for benefit. Using a Bayesian trial design, the authors go to impressive measures in justifying their early stoppage, and given their results, it was likely appropriate. But despite giving themselves a priori statistical permission for such a termination, as with any early stoppage, the potential for falsely optimistic results is high.

Finally, the authors failed to inform us how many patients were screened in the process of recruiting this cohort of 207 patients, so it is unclear how to place this trial in its appropriate context. I suspect, like the remainder of the endovascular trials, this was a highly selected cohort plucked from a far greater population of stroke patients.

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Far from Novel

Despite these issues, the results of the DAWN trial are far from novel findings. In fact, the trial is fairly consistent with the remainder of the literature examining endovascular therapy for treating acute ischemic stroke. When these therapies are deployed in a population of stroke patients with accessible lesions and salvageable tissue, patients fare notably better than controls.

The results of the DAWN cohort highlight the flaws in a selection process that utilizes an empiric time threshold to identify a cohort who will benefit from acute reperfusion therapy. The utilization of empiric time cutoffs is a remnant of an older age before we had wide access to perfusion imaging. The early studies examining the utility of perfusion imaging were consistently negative. But it is important to understand the context in which they failed to demonstrate a benefit.

The 1995 NINDS trial group published its findings describing the benefits of the use of tPA in patients presenting in under three hours. Shortly after the FDA approved the use of tPA in this subset of stroke patients, further attempts to validate its use in this subgroup of patients ceased. The early studies examining the use of perfusion imaging were not intended to further refine which patients would truly benefit from effective reperfusion therapy, but rather were utilized by industry as a ploy to potentially expand the window for administering thrombolytics, an agent of questionable therapeutic benefit.

If your reperfusion therapy lacks the ability to reperfuse, does it matter if you identify patients with salvageable brain tissue? What the endovascular trials have consistently demonstrated is that it is possible to identify a cohort of patients who will benefit from revascularization independent of time from symptom onset when perfusion imaging is paired with an effective therapeutic modality.

Given the success of the DAWN trial, it is time to re-examine the utility of thrombolytics when given in concert with endovascular therapies. What added benefit do they provide, if any? Given the current industry-driven trial climate and the fact that such a scientific inquiry can only harm Big Pharma's bottom line, it is doubtful such an endeavor will ever be carried out.

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