To enchant, from the Latin incant?re, meaning to be put under a spell. I will leave it to the insightful reader to interpret its meaning in the current context.
Needless to say when the authors of the Enhanced Control of Hypertension and Thrombolysis Stroke or ENCHANTED study endeavored to examine the efficacy of tPA in acute ischemic stroke, they selected their trial name appropriately.
Anderson et al examined 3,206 adult patients presenting to the Emergency Department with acute ischemic stroke within 4.5 hours of symptom onset, and randomized them to either standard-dose alteplase (0.9 mg/kg) or a low-dose strategy (0.6 mg/kg)(1).
The authors found that the number of patients who were dead or disabled (a mRS of 2-6) at 90-days was 53.2% and 51.1% in the low-dose and standard-dose groups respectively. This produced an odds ratio of 1.09 for increased risk death or disability in the patients who received the low-dose tPA. The 95%-confidence intervals surrounding this point estimate were 0.95 t0 1.25. Because the upper limit of this confidence interval crossed the predetermined non-inferiority margin of 1.14 the authors were unable to demonstrate non-inferiority. And while these findings initially appear grim for the low-dose strategy, in reality its utility is likely far more promising.
Despite this statistical failure, low-dose tPA performed admirably when compared to its standard-dose comparator. The number of patients alive and independent (mRS of 0,1,or 2) at 90 days was 62.4% and 63% in the low-dose and standard-dose groups respectively. In fact, at both 7 and 90 days, patients randomized to receive standard-dose thrombolytic died more frequently than those who received the low-dose strategy. Death at 7-days occurred in 60 patients (3.6%) in the low-dose cohort compared to 87 (5.3%) in the full-dose group. This 1.7% increase reached statistical significance with a p-value of 0.02. At 90-days the mortality was 8.5% vs 10.3% respectively. Furthermore, patients randomized to the standard-dose group experience higher rates of intracerebral hemorrhage (ICH). Major symptomatic ICH, according to SITS-MOST criteria, occurred in 1.0% of the patients in the low-dose group and in 2.1% of those in the standard-dose group. Fatal ICH occurred in 2.5% and 1.3% of the standard and low-dose groups respectively.
Once again we are faced with a trial examining the efficacy of tPA in acute ischemic stroke where reality and the statistical manner in which it is presented appear distinctly different. Despite the low-dose tPA group outperforming its full-dose comparator in almost every measure, this was a negative trial. This failure is based on how these authors defined success and our continued reliance on hypothesis testing.
Typically, a non-inferiority trial is performed to ensure that a new treatment strategy is no worse than the current strategy. This is statistically defined as a threshold below which the novel strategy cannot be considered non-inferior.This threshold is typically set by the authors conducting the trial(2). In this case the authors selected their non-inferiority margin at an odds ratio of 1.14. This number is based of the 2014 Cochrane analysis examining the efficacy of IV tPA vs placebo in acute ischemic stroke (3). In which, Wardlaw et al cite an odds ratio of 1.24 for increased death or disability in the patients randomized to receive placebo when compared to those who received IV tPA. Using this number as their guide, Anderson et al estimated that to ensure low -dose tPA retains at least half the efficacy of the standard dosing strategy, a threshold of 1.14 should not be crossed.
Because the upper limit of the 95%-confidence interval crosses the 1.14 threshold, the authors were unable to demonstrate non-inferiority. But failing to demonstrate non-inferiority is not equivalent to proving superiority. In fact, the authors were unable to demonstrate a statistical superiority of either treatment strategy when examining their primary endpoint. The authors found a 2.1% absolute difference in the incidence of death or disability between the two groups in favor of the standard dose tPA. The 95%-CI surrounding this point estimate is -1.4%-5.6%.
Despite its statistical failure, the ENCHANTED trial clearly demonstrates that reduced-dose tPA achieves similar clinical outcomes while decreasing death and ICH. But this exercise distracts us from the more important question, what is the optimal dosing strategy of IV tPA? As some of us still believe, and the data would suggest, a further reduction in dosing may be equally potent. A serial dilution until all that remains is the essence of the tPA that once was. This no-dose strategy, may further decrease the rates of symptomatic intracerebral hemorrhage and death with no noticeable difference in neurological outcomes. Enchanting indeed…
- Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med. DOI: 10.1056/NEJMoa1515510
- Kaul S, Diamond GA. Good Enough: A Primer on the Analysis and Interpretation of Noninferiority Trials. Ann Intern Med. 2006;145:62-69
- Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischae- mic stroke. Cochrane Database Syst Rev 2014;7:CD000213.
University of Maryland
Resuscitation Fellowship Graduate