Josh Farkas (@PulmCrit) recently posted a brilliant reanalysis of the NINDS trial using a metric known as Fragility Index . Fragility Index measures the statistical reproducibility of a trial by determining the minimal number of patient outcomes that must be changed in order to shift the p-value above 0.05. The smaller the Fragility Index, the more fragile the study. Although this concept is relatively new, it has already been used to evaluate a large number of trials in the critical care setting .
Calculating the Fragility Index of ECASS III
ECASS III assessed the efficacy and safety of tPA administered between 3 and 4.5 hours after the onset of stroke symptoms and provided the rationale for the “extended treatment window” in current practice guidelines. The authors concluded that more patients had a favorable outcome with alteplase vs. placebo (52.4% vs. 45.2%; OR, 1.34; 95% CI 1.02-1.76, P = 0.04). These results are depicted in the table below.
- Fragility Index measures the statistical reproducibility of study outcomes. A low Fragility Index indicates less statistically robust results.
- ECASS III has a Fragility Index of one, meaning it would only take one additional favorable outcome in the control group to render a nonsignificant difference between tPA and placebo.
- Similar to the NINDS trial, ECASS III has an extremely low Fragility Index which suggests that the "beneficial" results of these studies are likely not reproducible.
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- Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke. N Engl J Med 2008;359:1317-29.
- http://www.thennt.com/nnt/thrombolytics-for-stroke/. Accessed electronically August 2, 2016.
- Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2013;44:870-947
- http://emcrit.org/pulmcrit/fragility-index-ninds/. Accessed electronically August 2, 2016.
- Ridgeon EE, Young PJ, Bellomo R, et all. The Fragility Index in Multicenter Randomized Controlled Critical Care Trials. Crit Care Med 2016;44(7):1278-84.
- http://www.fragilityindex.com. Accessed electronically August 2, 2016.
- Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department. Ann Emerg Med 2015;66:322-333.