Low-Dose vs Standard-Dose Alteplase for Patients With Acute Ischemic Stroke: Secondary Analysis of the ENCHANTED Randomized Clinical Trial

Abstract

Importance: A lower dose of intravenous alteplase appears to be a safer treatment option than the standard dose, reducing the risk of symptomatic intracerebral hemorrhage. There is uncertainty, however, over how this effect translates into an overall clinical benefit for patients with acute ischemic stroke (AIS).

Objective: To assess whether older, Asian, or severely affected patients with AIS who are considered at high risk of thrombolysis may benefit more from low-dose rather than standard-dose alteplase treatment.

Design, setting, and participants: This study is a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, randomized, open-label, blinded, end-point clinical trial of low-dose vs standard-dose intravenous alteplase for patients with AIS. From March 1, 2012, to August 31, 2015, a total of 3310 patients who had a clinical diagnosis of AIS as confirmed by brain imaging and who fulfilled the local criteria for thrombolysis treatment were included in the alteplase-dose arms. Patients were randomly assigned to receive low-dose (0.6 mg/kg; 15% as bolus and 85% as infusion over 1 hour) or standard-dose (0.9 mg/kg; 10% as bolus and 90% as infusion over 1 hour) alteplase. Of the 3310 randomized patients, 13 patients were excluded for missing consent, mistaken randomization, and duplicate randomization numbers. This secondary analysis was conducted between May 1, 2016, and April 28, 2017.

Main outcomes and measures: The primary end point was a poor outcome defined by the combination of death and any disability as scored by the modified Rankin Scale (scores range from 2 to 6, with the highest score indicating death) at 90 days.

Results: Of the 3297 patients included in the analysis, 1248 (37.9%) were women, and the mean (SD) age was 67 (13) years. No significant differences in the treatment effects were observed between low- and standard-dose alteplase for poor outcomes (death or disability) by age, ethnicity, or severity (all P > .37 for interaction). Similarly, the treatment effects of low- vs standard-dose alteplase on function outcome (ordinal shift of the modified Rankin Scale) in Asians (odds ratio, 1.05; 95% CI, 0.90-1.22) was consistent with non-Asians (odds ratio, 0.93; 95% CI, 0.76-1.14) (P = .32 for interaction). There were generally consistent reductions in rates of symptomatic intracerebral hemorrhage with low-dose alteplase, although this reduction was not statistically significant by age, ethnicity, or severity.

Conclusions and relevance: This analysis found that the effects of low-dose alteplase were not clearly superior to the effects of standard-dose alteplase on death or disability in key demographic subgroups of patients with AIS. Further investigation is required to identify patients with AIS who may benefit from low-dose alteplase.

Trial registration: clinicaltrials.gov Identifier: NCT01422616.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Robinson reported being a National Institute for Health Research senior investigator and receiving speaking fees from Bayer and Boehringer Ingelheim, as well as fees from Bayer and Daiichi Sankyo for participating in advisory panels. Dr Bath reported receiving grants from the George Institute for Global Health and the University of Sydney; being a National Institute for Health Research senior investigator; receiving fees from Athersys, Covidien, Nestlé, Phagenesis, and ReNeuron for participating in advisory panels; and being an unpaid director of Platelet Solutions. Dr Broderick reported receiving research monies from Genentech, consulting fees from Pfizer, and fees for advisory board participation from AstraZeneca. Dr Demchuk reported receiving honoraria from Medtronic, Pfizer/Bristol-Myers Squibb, AstraZeneca, and Bayer for continuing medical education and honoraria from Pfizer/Bristol-Myers Squibb, Bayer, and AstraZeneca for advisory board participation. Dr Donnan reported receiving a grant from the Australian National Health and Medical Research Council and payment for advisory board participation from AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Merck Sharpe Dohme, Pfizer, and Servier. Dr Lavados reported receiving grants and personal fees from the George Institute for Global Health, Clinica Alemana de Santiago, Bayer, and AstraZeneca; grants from Comisión Nacional de Investigación Científica y Tecnológica; and nonfinancial support from Boehringer Ingelheim. Dr Lindley reported receiving speaking fees from Boehringer Ingelheim, Covidien, and Pfizer. Dr Olavarria reported receiving research funding from the George Institute for Global Health and from Clinica Alemana de Santiago. Dr Pontes-Neto reported receiving speaking fees from Boehringer Ingelheim and Medtronic. Dr Ricci reported receiving fees from Boehringer Ingelheim and Medtronic. Dr Woodward reported being a consultant for Amgen. Dr Anderson reported receiving fees from AstraZeneca and Medtronic for participating in advisory panels, from Takeda China and Boehringer Ingelheim for speaking at seminars, and a research grant from Takeda China. Dr Chalmers reported receiving research grants and lecture fees from Servier for the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial and posttrial follow-up. No other disclosures were reported.

Figures

Figure 1.. Randomized Treatment Effects on Death or Disability at 90 Days by Age, Ethnicity, and Stroke Severity

Solid boxes represent estimates of treatment effect; horizontal lines, 95% CI; and diamond, the estimate and 95% CI for the overall effect. Areas of the boxes are proportional to the number of outcomes. NIHSS indicates National Institutes of Health Stroke Scale; OR, odds ratio. aData from Figure 2 in Anderson et al.

Figure 2.. Randomized Treatment Effects on Symptomatic Intracerebral Hemorrhage by Age, Ethnicity, and Stroke Severity

Treatment effects on symptomatic intracerebral hemorrhage are presented by age (A), ethnicity (B), and stroke severity (C). Solid boxes represent estimates of treatment effect; horizontal lines, 95% CI; and diamond, the estimate and 95% CI for the overall effect. Areas of the boxes are proportional to the number of outcomes. ECASS indicates European Cooperative Acute Stroke Study; IST, International Stroke Trial; NIHSS, National Institutes of Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; OR, odds ratio; and SITS-MOST, Safe Implementation of Thrombolysis in Stroke Monitoring Study. aData from Figure S8 of the Supplementary Appendix in Anderson et al.

Figure 3.. Randomized Treatment Effects on Functional Outcome According to the Modified Rankin Scale at 90 Days, by Ethnicity

Scores on the modified Rankin Scale (mRS) range from 0 to 6, with 0 indicating no symptoms; 1, symptoms without significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death. OR indicates odds ratio.