Stroke

ENCHANTED trial

The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) was driven by concerns about safety of intravenous alteplase in terms of hemorrhages, especially in Asians. The study compared the standard dose of 0.9 mg/kg of alteplase with a low dose of 0.6 mg/kg in acute ischemic stroke with the aim to improve efficacy and safety of intravenous thrombolysis.

Authors: Simona Sacco, Milija Mijajlovic, Thorsten Steiner

Reviewer’s/Authors’ affiliation
Institute of Neurology, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, L’Aquila, Italy (SS)
Neurology Clinic, Clinical Center of Serbia and School of Medicine University of Belgrade, Serbia (MM)
Department of Neurology, Klinikum Frankfurt Höchst, and Heidelberg University Hospital, German (TS)

Pubmed / web link(s) to the work reviewed/cited.
C.S. Anderson, T. Robinson, R.I. Lindley, H. Arima, P.M. Lavados, T.-H. Lee, J.P. Broderick, X. Chen, G. Chen, V.K. Sharma, J.S. Kim, N.H. Thang, Y. Cao, M.W. Parsons, C. Levi, Y. Huang, V.V. Olavarría, A.M. Demchuk, P.M. Bath, G.A. Donnan, S. Martins, O.M. Pontes‑Neto, F. Silva, S. Ricci, C. Roffe, J. Pandian, L. Billot, M. Woodward, Q. Li, X. Wang, J. Wang, and J. Chalmers, for the ENCHANTED Investigators and Coordinators. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. NEJM DOI: 10.1056/NEJMoa1515510
ClinicalTrials.gov, number NCT01422616

Comment: 150-250 words.
The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) was driven by concerns about safety of intravenous alteplase in terms of hemorrhages, especially in Asians. The study compared the standard dose of 0.9 mg/kg of alteplase with a low dose of 0.6 mg/kg in acute ischemic stroke with the aim to improve efficacy and safety of intravenous thrombolysis.
The study involved 3,310 patients from 111 clinical centers in 13 countries; 2/3 of patients came from Asia. The primary objective was to determine the non-inferiority of the low dose as compared to the standard dose in terms of efficacy measured with rates of deaths and disability at 3 months. The primary outcome occurred in 53.2% of patients treated with the low dose and in 51.1% of patients treated with the standard dose (odds ratio 1.09; 95% confidence interval 0.95-1.25, P=0.51). This result did not meet the non-inferiority criterion.
The secondary analysis showed that the low dose was safer than standard dose in terms of occurrence of symptomatic intracerebral hemorrhage (1.0 % vs. 2.1%; low dose vs. standard dose), odds ratio 0.48; 95% confidence interval 0-27-0.86, P=0.01). Additionally, the distribution of the modified Rankin scale scores at 90 days indicated a lower rate of deaths with the low dose (8.7% vs. 10.6%) accompanied by more patients surviving with mild to moderate grades of residual disability.  Subgroup analyses showed no age relationship with treatment and no heterogeneity of treatment effect according to ethnicity (Asians versus non-Asians).
Possible practical implications coming from the ENCHANTED trial are not defined yet as revision of the available guidelines is awaited. At the moment, the low dose may be preferred in selected patients at high risk of bleeding as it may lower the risk of intracerebral hemorrhage without compromising efficacy too much.

References
Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med. DOI: 10.1056/NEJMoa151551

Key points: 3-5
1.    In patients with acute ischemic stroke eligible for intravenous thrombolysis, a low dose of alteplase (0.6 mg/kg) is not non-inferior to the standard dose (0.9 mg/kg)
2.    In patients with acute ischemic stroke eligible for intravenous thrombolysis, a low dose of alteplase (0.6 mg/kg) is safer in terms of intracerebral hemorrhage rates as compared to the standard dose (0.9 mg/kg)
3.    In patients with acute ischemic stroke eligible for intravenous thrombolysis, a low dose of alteplase (0.6 mg/kg) as compared to the standard dose (0.9 mg/kg) reduces deaths but this is offset by an increase in disability
4.    A low dose of alteplase (0.6 mg/kg) is still not recommended for a routine clinical practice in patients with acute ischemic stroke who are eligible for intravenous thrombolysis while current guidelines recommend the standard dose of alteplase (0.9 mg/kg)