Lower Dose of tPA Found Safer For Patients With Acute Ischemic Stroke

MedicalResearch.com Interview with:

Professor Craig Anderson Professor of Stroke Medicine and Clinical Neuroscience Sydney Medical School at the University of Sydney Institute of Neurosciences of Royal Prince Alfred Hospital

Prof. Craig Anderson

Professor Craig Anderson
Professor of Stroke Medicine and Clinical Neuroscience
Sydney Medical School at the University of Sydney
Institute of Neurosciences of Royal Prince Alfred Hospital

MedicalResearch.com: What is the background for this study?

Prof. Anderson: Intravenous use of the clot-busting drug, alteplase (or rtPA), at a dose of 0.9 mg/kg body weight is the only proven medical treatment of acute ischemic stroke.  However, a  major drawback to the treatment is an increased risk of major bleeding in the brain, or intracerebral hemorrhage (ICH), that occurs in about 5% of cases, and can be fatal.  This balance of effectiveness (recovery from disability) and risks (ICH, and bleeding elsewhere and uncommon drug allergic reactions) has led to much of the controversy over the net benefit of the drug.  The optimal dose of the drug has never been established, but the Japanese drug safety regulatory authority, has approved a lower dose (0.6mg/kg) on the basis of a small, non-randomized, open study which showed comparable outcomes and lower risk of ICH than historical controls.  This ‘east-west’ divide over the approved dose of alteplase has led to much variation in the dose of alteplase used in clinical practice in Asia – according to a doctor’s perceived risk of ICH in individual patients and the affordability of this relatively expensive treatment in low resource settings.  Data from the Get-with-the Guidelines Quality Registry in the United States suggests Asian patients are at higher risk of ICH after standard-dose alteplase than non-Asians.

Our research aimed to resolve this uncertainty over the optimal dose of alteplase, as an international, active-comparator, open-label, blinded outcome assessed, clinical trial of low-dose (0.6 mg/kg) versus standard-dose (0.9mg/kg) in 3310 patients recruited from over 100 hospitals in 13 countries between 2012 and 2015.

MedicalResearch.com:? What are the main findings?

Prof. Anderson: The study showed that low-dose alteplase was safer than standard-dose alteplase, with lower rates of ICH across all of the measures taken of this endpoint, and this translated into improved survival.  However, survivors of low-dose alteplase has slightly more mild-moderate level of residual disability than survivors of standard-dose alteplase.  On the conventional binary measure of ‘recovery’ that is often used in acute stroke clinical trials, the study failed to show that low-dose alteplase was not inferior to standard-dose alteplase, but across more modern measures that take account of a patients overall level recovery, the two doses were essentially equivalent, with quality of life being similar for patients in both dose-groups at 3 months after receiving alteplase.

The study raises clinical and ethical issues about how clinicians, patients and families, assess the potential benefits against potential risks of altelplase in critical illness of acute stroke.

MedicalResearch.com: What should readers take away from your report?

Prof. Anderson: A lower dose of intravenous alteplase is a safer treatment for patients with acute ischemic stroke and retains much of the lytic effects as the standard dose of alteplase

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Prof. Anderson: The trial suggests the need for further medical approaches to clot-busting in acute ischemic stroke, for example in assessing the effects and risks of low-dose alteplase in combination with novel antithrombotics.

MedicalResearch.com: Is there anything else you would like to add?

Prof. Anderson: Contrary to popular belief, Asian patients in our research were no more at risk of ICH than non-Asian (‘white Caucasian’) patients, and the benefits of low-dose alteplase were comparable for different types of patients defined by age, race, time from symptom onset, and pathological type of ischemic stroke. 

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.


Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

Craig S. Anderson, M.D., Ph.D., Thompson Robinson, M.D., Richard I. Lindley, M.D., Hisatomi Arima, M.D., Ph.D., Pablo M. Lavados, M.D., M.P.H., Tsong-Hai Lee, M.D., Ph.D., Joseph P. Broderick, M.D., Xiaoying Chen, B.Pharm., B.Mgt., Guofang Chen, M.D., Vijay K. Sharma, M.D., Jong S. Kim, M.D., Ph.D., Nguyen H. Thang, M.D., Yongjun Cao, M.D., Ph.D., Mark W. Parsons, M.D., Ph.D., Christopher Levi, M.D., Yining Huang, M.D., Verónica V. Olavarría, M.D., Andrew M. Demchuk, M.D., Philip M. Bath, F.R.C.P., D.Sc., Geoffrey A. Donnan, M.D., Sheila Martins, M.D., Octavio M. Pontes-Neto, M.D., Federico Silva, M.D., Stefano Ricci, M.D., Christine Roffe, M.D., Jeyaraj Pandian, M.D., D.M., Laurent Billot, M.Sc., Mark Woodward, Ph.D., Qiang Li, M.Biostat., Xia Wang, M.Med., Jiguang Wang, M.D., Ph.D., and John Chalmers, M.D., Ph.D., for the ENCHANTED Investigators and Coordinators*

May 10, 2016DOI: 10.1056/NEJMoa1515510

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Last Updated on May 10, 2016 by Marie Benz MD FAAD