The question of alteplase dose for stroke is not resolved

Abstract

Welfare approved the use of the tissue plasminogen activator (tPA) alteplase for acute stroke at a dose of 0.6 mg/ kg within 3 h of onset, a lower dose than the standard of 0.9 mg/kg in Europe and the USA. The approval of this low dose was based on results of the Japan Alteplase Clinical Trial (J-ACT) 1 ; in this trial, the administered dose of 0.6 mg/kg alteplase was selected on the basis of previous studies that showed 0.6 mg/kg to be noninferior to 0.9 mg/kg in Japanese patients. The recently published Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) 2 , however, was not able to confirm that a dose of 0.6 mg/kg is noninferior to a dose of 0.9 mg/kg in Asian and non-Asian participants, raising questions about standard use of 0.6 mg/kg in Asian medical practice.The 1990s saw the publication of three randomized, double-blind trials of the tPA duteplase for embolic stroke in Japanese patients. A pilot study showed that a dose of 20 million international units (MIU) was superior to placebo 3 , and a subsequent randomized, double-blind, dose comparison study showed that a dose of 30 MIU did not further improve recanalization rates but increased the occurrence of massive brain haematoma formation and haemorrhagic transformation 4 . Furthermore, a study of alteplase for myo cardial infarction showed that the dose required for a coronary patency rate of 65-80% in Japanese patients Stroke-Non-European Union World study demonstrated the safety and efficacy of 0.9 mg/kg alteplase in an Asian population 9 .The ENCHANTED study was designed to compare the effects of low-dose (0.6 mg/kg) alteplase with those of standard-dose (0.9 mg/kg) alteplase in patients who were recruited at 111 clinical centres in 13 countries worldwide 2 . The prespecified primary outcome was the combined end point of death or disability at 90 days. Secondary outcomes included sICH, modified Rankin scale (mRS) scores at 90 days, and quality of life at 90 days. Outcomes were analysed with a linear regression model to test the accepted hypothesis that low-dose alteplase is noninferior to standarddose alteplase. To satisfy the hypothesis of noninferiority, the upper confidence interval of the odds ratio needed to be below 1.14 (a value derived from a Cochrane meta-analysis of alteplase trials).The primary outcome occurred in 53.2% of patients in the low-dose group, and in 51.1% in the standard-dose group (OR 1.09, 95% CI 0.95-1.25), a result that -owing to the confidence intervals -did not demonstrate that 0.6 mg/kg alteplase is noninferior to 0.9 mg/kg alteplase. However, low-dose alteplase was noninferior to standard-dose alteplase in the ordinal analysis of mRS scores and quality of life, and standard-dose alteplase was associated with higher risks of major sICH and death. The distribution of mRS scores in the two groups at 90 days indicated that the lower death rate seen with low-dose alteplase was accompanied by a greater degree of mild to moderately severe residual disability among survivors. Importantly, no differences wer...

Benefit of Intravenous Alteplase before Thrombectomy Depends on ASPECTS

“…[18][19][20] Since the approval of IVT for the treatment of ischemic stroke by the FDA in 1996, there has been a debate about the benefit and potential harm of IVT administration and about the optimal treatment candidate selection. [21][22][23][24][25][26][27] A previous comprehensive meta-analysis of individual patient data from randomized trials observed that IVT improves the overall odds of good outcomes when delivered within 4.5 hours, irrespective of age and NIHSS. 28 Regarding the degree of early ischemic changes, previous landmark trials evaluating the effect of IVT excluded patients with early ischemic changes in >1/3 of the MCA territory, while other studies concluded not to have enough statistical power to ascertain whether IVT adds risk or benefit (i.e., in patients with ASPECTS 0-7).…”

“…Since the approval of IVT for the treatment of ischemic stroke by the FDA in 1996, there has been a debate about the benefit and potential harm of IVT administration and about the optimal treatment candidate selection 21–27 . A previous comprehensive meta‐analysis of individual patient data from randomized trials observed that IVT improves the overall odds of good outcomes when delivered within 4.5 hours, irrespective of age and NIHSS 28 .…”

Effect of Intravenous Alteplase on Functional Outcome and Secondary Injury Volumes in Stroke Patients with Complete Endovascular Recanalization

“…Since approval of IVT for the treatment of ischemic stroke by the FDA in 1996, there has been an ongoing debate about harm and benefit of IVT administration and about the optimal treatment selection [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. In 2018, the WAKE-UP trial reported a beneficial treatment effect of IVT compared to placebo despite a slightly increased rate of sICH [ 34 ].…”