A low dose of tissue plasminogen activator (tPA, alteplase) was safer in terms of intracerebral hemorrhage (ICH) rates but missed the noninferiority criteria that made up the primary efficacy endpoint in the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial in patients with acute stroke.
The major secondary efficacy outcome was met, however.
The results were presented this week at the European Stroke Organisation Conference (ESOC) 2016 in Barcelona, Spain, and simultaneously published online in the New England Journal of Medicine (NEJM).
Presenting the results at the ESO conference, Craig Anderson, MD, University of Sydney, Australia, concluded: "The 0.6 mg/kg low dose of tPA reduced deaths, but this was offset by an increase in disability. If 1000 patients were treated with the low dose instead of standard dose, this would save 19 lives but leave 40 additional patients with mild to moderate disability."
"In terms of safety, ICH rates were halved and there is no doubt that the low dose is safer," he added.
Conference chair, Ken Lees, MD, University of Glasgow, United Kingdom, described the ENCHANTED results as "fascinating."
"Although the primary outcome was not statistically significant, these are very interesting intriguing findings that could change practice," he told Medscape Medical News.
The trial compared standard-dose tPA (0.9 mg/kg) with a new low dose (0.6 mg/kg) in 3310 patients who were within 4.5 hours of the onset of stroke. Median age of patients included was 67 years; 63% were Asian.
The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability (scores of 2 to 6 on the modified Rankin scale [mRS]) at 90 days.
This primary outcome occurred in 53.2% of the low-dose group and in 51.1% of the standard-dose group (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.95 - 1.25). The upper boundary exceeded the noninferiority margin of 1.14; and the P value for non-inferiority was 0.51.
However, the low dose did meet noninferiority criteria for the secondary outcome of the ordinal analysis of mRS scores (OR, 1.00; 95% CI, 0.89 - 1.13; P = .04 for noninferiority).
Results also showed greater safety in terms of major symptomatic ICH with the low dose (1.0% vs 2.1%; P = .01 for superiority). Death at 7 days was also reduced with the low dose (0.5% vs 1.5%; P = .01 for superiority). Mortality at 90 days did not differ significantly between the two groups (8.5% vs 10.3%, respectively; P = .07 for superiority).
In the NEJM paper, the ENCHANTED authors explain that the trial was driven by concern about high risks for ICH with tPA, particularly among Asians. "Using several definitions of symptomatic ICH we observed fewer clinically important cases in the group assigned to low-dose alteplase than in the group assigned to standard-dose alteplase, and the difference in risk was consistent in Asians and non-Asians," they write.
There was no heterogeneity of treatment effect on the primary outcome in prespecified subgroups, such as Asians vs non-Asians and those receiving antiplatelet agents, but the authors point out that these analyses had low statistical power.
"The low dose was associated with a reduced mortality but some increase in disability, but this was at the more mild end of the disability spectrum," ENCHANTED investigator, Thompson Robinson, MD, University of Leicester, United Kingdom, commented to Medscape Medical News.
"In my view the results need to be discussed between guidelines committees, clinicians and patients," he added. "But if your main aim is to reduce death and bleeding, then our results show that low dose is a safer treatment. In addition, it may be a better treatment for patients with other factors that increase the risk of bleeding or death."
"But if overall the patient wants the best chance of being completely independent then the standard dose may be preferable. There are two messages there — it is very dependent on what individual patients and clinicians think. These results will give clinicians and guidelines committees a lot to consider."
Outside commentators had mixed reactions to the results.
"The low dose definitely looked safer, but there is always reluctance to change guidelines if the primary endpoint was not met, so it is unlikely to become the new standard in my opinion," Clay Johnston, MD, Dell Medical School, University of Texas, Austin, said. "However, it does make sense to use the lower dose if you're concerned about hemorrhage, and I'm sure many clinicians will do just that."
Peter Rothwell, MD, University of Oxford, United Kingdom, believes the ENCHANTED trial has shown "a very helpful result."
He explained to Medscape Medical News that many Asian countries are already using low-dose tPA, and "this is a very helpful validation of that approach." He added that, "those of us in Western countries will be reassured to know we can use a lower dose for greater safety without compromising efficacy too much This will be especially useful in selected patients at high risk of bleeding."
"No Compelling Evidence"
However, the author of an accompanying editorial in the NEJM takes a much stricter view. Cathy Sila, MD, University Hospitals–Case Medical Center, Cleveland, Ohio, makes the point that the ENCHANTED trial was not designed with sufficient power to evaluate the outcomes in Asian vs non-Asian patients, "but 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."
Hemorrhage contributed to early death, but mortality was similar in the two groups at 90 days, and most deaths were due to the index ischemic stroke, she adds.
She concludes that: "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."
"It's tempting to see things the way you wish they were instead of how they are," she writes, citing a quote from the Disney movie Enchanted.
"ENCHANTED shows us how things really are and supports the continued use of guideline-based thrombolytic therapy for Asians with acute stroke."
European Stroke Organisation Conference (ESOC) 2016. Presented May 10, 2016.
N Engl J Med. Published online May 10, 2016. Full text Editorial
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Cite this: ENCHANTED: Low-Dose tPA Now a Viable Option in Stroke? - Medscape - May 11, 2016.