I am probably the last person to comment on ENCHANTED, the trial testing low-dose vs. standard-dose tPA in “Asians”. When it was released, to some fanfare in the New England Journal of Medicine, I had little to say – it is, frankly, a rather bland contribution to the science. What has been fascinating, however, is the unusually divergent interpretation of the results. To wit, the accompanying editorial in the NEJM states:
“ENCHANTED provides no compelling evidence for using low-dose alteplase for acute ischemic stroke in Asian or other populations on the basis of safety considerations or clinical outcomes.”
This is a relatively reasonable interpretation of the results – hinging on the word “compelling”. No one’s hearts are to be set a-flutter over these results, but that does a disservice to the ultimate clinical question of which dose is appropriate. The lay press, however, is here to clear things up – or is it?
“ENCHANTED: Low-Dose tPA Now a Viable Option in Stroke?”
“ENCHANTED results challenge reduced alteplase dose in Asian stroke patients”
“Low-Dose tPA Not as Effective, Even for Asians”
“Lower Dose of Clot-Busting Drug Reduces Brain Bleeding”
“Low-dose alteplase fails to prove noninferiority to standard dose, shows some benefit in stroke”
“Low-Dose Alteplase Not as Effective as Standard-Dose in Acute Ischemic Stroke”
The question, simply, comes down to how easily one interprets “non-inferiority” – a point made nicely by Rory Spiegel in his post – and, further, how one interprets these findings in a Bayesian sense. The prevailing opinion going into this trial was that low-dose tPA was safer and similarly efficacious in certain ethnic subpopulations on the Asian continent. The nonsignificant difference (OR 1.09; 95% CI 0.95 to 1.25) in patients having excellent outcomes (mRS 0-1) and the even smaller difference (OR 1.03; 95% CI 0.89 to 1.19) in those having good outcomes (mRS 0-2) does nothing to move the needle on the prevailing clinical hypothesis. If there is unlikely to be a profound difference in clinical outcomes, what of the safety outcomes? Here, low-dose alteplase is obviously a winner – significant reductions in hemorrhage and a corresponding decrease in 90-day mortality (p=0.07).
If ECASS failed gloriously due to adverse effects at 1.1 mg/kg, subsequent trials found some favorable risk/benefit at 0.9 mg/kg, and the (supposed) clinical efficacy seems preserved with even greater safety at 0.6 mg/kg, it seems logical to expand interest in lower doses of tPA. I disagree with those who would dismiss this trial as an unimportant “failure”.
“Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke”
http://www.nejm.org/doi/full/10.1056/NEJMoa1515510