Low-Dose tPA Not as Effective, Even for Asians

No clue what non-inferiority means, you'll have to assume your doctor can decipher this research.

http://www.medpagetoday.com/Cardiology/Strokes/57831?

Fewer brain bleeds in trial but misses non-inferiority on outcomes

Low-dose tissue plasminogen activator (tPA) was not as good as standard dosing, despite being associated with fewer hemorrhagic complications, in the ENCHANTED trial among a mainly Asian population.
The primary outcome of 90-day death or disability, defined by scores of 2 to 6 on the modified Rankin scale, occurred in 53.2% of patients given IV alteplase (Activase) at 0.6 mg/kg, compared with 51.1% among patients given the standard 0.9-mg/kg dose.
That yielded an odds ratio of 1.09, for which the 95% confidence interval of 0.95 to 1.25 exceeded the non-inferiority margin (P=0.51 for non-inferiority), Craig S. Anderson, MD, PhD, of the University of Sydney, and colleagues reported online in the New England Journal of Medicine. The findings were presented simultaneously at the European Stroke Organization Conference in Barcelona.
Other findings showed that low-dose versus standard-dose use yielded:

• Non-inferiority for nominal modified Rankin scale scores (P=0.04 for non-inferiority)
• Fewer major symptomatic intracerebral hemorrhages (1.0% versus 2.1%, P=0.01)
• Fewer fatal events occurred within 7 days (0.5% versus 1.5%, P=0.01)
• No difference in mortality at 90 days (8.5% versus 10.3%, P=0.07)

"Our trial was driven by concern about high risks of intracerebral hemorrhage with alteplase, particularly among Asians, because preliminary studies have had differing results with respect to the effectiveness and risks of this treatment," the researchers noted.
For instance, "the Japanese drug safety authority has approved the use of alteplase at a dose of 0.6 mg per kilogram after an uncontrolled, open-label study showed that this dose resulted in equivalent clinical outcomes and a lower risk of intracerebral hemorrhage than that reported in published studies in which the 0.9-mg-per-kilogram dose was used.
"Other registry studies in Asia have shown inconsistent results, but a high risk of symptomatic intracerebral hemorrhage was observed among Asian patients treated with 0.9 mg of alteplase per kilogram in the United States."
But no significant interactions were observed in Anderson's trial between Asians and non-Asians, although the trial had low statistical power to look for a difference.
Even so, "the low rates of hemorrhage and lack of significant interaction with ethnic group argue against a substantially increased risk that would preclude standard-dose therapy," Cathy Sila, MD, of University Hospitals-Case Medical Center in Cleveland wrote in an accompanying editorial.
"This large, randomized trial provides more robust data to guide care than the previous recommendations based on registry data," she concluded, adding, "ENCHANTED shows us how things really are and supports the continued use of guideline-based thrombolytic therapy for Asians with acute stroke."
The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial included 3,310 patients eligible for thrombolytic therapy (median age 67; 63% Asian) in a 2-by-2 quasi-factorial open-label design randomized to alteplase dose within 4.5 hours of stroke onset.
Aside from the open-label design, the researchers cautioned about selection bias from "inclusion of patients who had a predominantly mild severity of neurologic impairment and who were treated at a later time point after symptom onset than in other trials and than in quality-assurance studies of the use of alteplase in patients with acute ischemic stroke."
"The high percentage of Asian participants and concurrent intensive blood-pressure control in some patients may also raise concerns about generalizability," they added.