Low-dose alteplase fails to prove noninferiority to standard dose, shows some benefit in stroke

Low-dose alteplase was inferior to standard-dose alteplase at preventing death or disability at 90 days in patients with acute ischemic stroke, according to the results of the ENCHANTED trial.

However, low-dose alteplase (Activase, Genentech) was associated with reduced risk for symptomatic intracerebral hemorrhage and for fatal events at 7 days, according to the researchers.

“Most patients who have a major stroke want to know they will survive but without being seriously dependent on their family. We have shown this to be the case with the lower dose of the drug,” Thompson (Tom) Robinson, MD, from the department of cardiovascular sciences at the University of Leicester, United Kingdom, said in a press release.

Thompson Robinson

The researchers presented the findings at the European Stroke Organisation Conference and published them in The New England Journal of Medicine.

Craig S. Anderson, MD, PhD, and colleagues randomly assigned 3,310 patients (median age, 67 years; 63% Asian) eligible for thrombolytic therapy within 4.5 hours after stroke onset to low-dose alteplase (0.6 mg/kg of body weight) or standard-dose alteplase (0.9 mg/kg of body weight).

The primary outcome was death or disability, defined as a score of 2 to 6 on the modified Rankin scale, at 90 days. To show noninferiority for the low-dose regimen, the upper bound of the 95% CI for the primary outcome could not exceed 1.14. Secondary outcomes included superiority for prevention of symptomatic intracerebral hemorrhage and noninferiority in an ordinal analysis of scores from the modified Rankin scale.

Noninferiority not met

Anderson, from The George Institute for Global Health in Sydney, Australia, and colleagues found that the primary outcome occurred in 53.2% of the low-dose group and 51.1% in the standard-dose group (OR = 1.09; 95% CI, 0.95-1.25). Because the upper bound of the 95% CI of 1.25 exceeded the noninferiority margin of 1.14, noninferiority was not shown (P for noninferiority = .51).

When the researchers performed an ordinal analysis of modified Rankin scale scores, they found the low dose was noninferior (unadjusted common OR = 1; 95% CI, 0.89-1.13; P for noninferiority = .04).

Major symptomatic intracranial hemorrhage was lower in the low-dose group (1% vs. 2.1%; P = .01), as was fatal events within 7 days (0.5% vs. 1.5%; P = .01), according to the researchers.

At 90 days, there was no significant difference in mortality between the low-dose group (8.5%) and the standard-dose group (10.3%; P = .07).

“What we have shown is that if we reduce the dose level, we maintain most of the clot-busting benefits of the higher dose but with significantly less major bleeds and improved survival rates,” Anderson said in the release. “On a global scale, this approach could save the lives of many tens of thousands of people. There is a tradeoff with the lower dose in regards to recovery of functioning, but being alive is surely preferable to most patients than suffering an early death.”

No compelling evidence

However, in a related editorial, Cathy Sila, MD, wrote 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.”

Sila, from the department of neurology at University Hospitals Case Medical Center, Cleveland, concluded that, “Using less effective therapies to save short-term costs will only increase the costs of long-term care for disabled stroke survivors.”

The ENCHANTED trial had a two-by-two factorial design in which 935 patients also were randomly assigned to intensive or guideline-recommended BP control. The BP-control portion of the study is scheduled to be completed in 2018, the researchers wrote in The New England Journal of Medicine. – by Erik Swain

References:

Anderson CS, et al. Official Welcome and Large Clinical Trials. Presented at: European Stroke Organisation Conference; May 10-12, 2016; Barcelona, Spain.

Anderson CS, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1515510.

Sila C. N Engl J Med. 2016;doi:10.1056/NEJMe1605228.

Disclosure: Anderson reports receiving personal fees from AstraZeneca and Medtronic and personal fees and nonfinancial support from Takeda China. Robinson reports receiving personal fees from Bayer, Boehringer Ingelheim and Daiichi Sankyo. Please see the full study for a list of the other researchers’ relevant financial disclosures. Sila reports receiving grant support from Stryker.