A recent trial published in May in the New England Journal of Medicine (NEJM) has clinicians wondering if we have a better option for patients suffering from acute ischemic stroke. The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED),1 a large randomized trial looking at acute blood pressure management and a lower dose of alteplase (tPA) in patients with acute ischemic stroke, published data regarding the thrombolysis portion of the trial with the analysis of blood pressure management intervention expected to be completed in 2018.
The study was born of the notion that patients of Asian descent are at higher risk of bleeding complications from tPA. Creeping was the suspicion that Japanese guidelines recommended a lower dose of tPA since at least 2011 (which corresponds to when Japanese guidelines were first available in English) based on 2 small (50-100 patients), non-blinded, prospective studies in Japanese patients showing equal efficacy and lower complication rate.2-4 In a letter to the editor of NEJM written by clinicians from Singapore in 2010, practical implementation of a low tPA strategy did not reproduce the expected results, anecdotally questioning the generalizability of Japanese data to other Asian countries.5
The ENCHANTED trial is the first to provide randomized and blinded data exploring the issue. Designed as a non-inferiority trial, the primary end-point of death and disability at 90 days was not met, failing to demonstrate that a lower dose of tPA was non-inferior to current standard practices among a mostly Asian cohort of mild acute ischemic stroke. Secondary endpoint results were significant for no difference in the distribution of modified Rankin scale scores at 90 days (meeting non-inferiority thresholds), less mortality at 7 days in the low dose group, and less symptomatic intracerebral hemorrhage in the low dose group (1.1% vs 2%).
It may be tempting to conclude from secondary outcome measures that low dose tPA is a safer option, intoxicated by the allure of cost savings and lower complication rates. In an accompanying editorial, Cathy Sila, MD, Director of the Comprehensive Stroke Center at University Hospitals Case Medical Center, gave a sober and thorough assessment to the contrary.6 Her insights highlight that while the trial was not powered to compare outcomes in Asian vs non-Asian study participants, no significant interactions between race and outcome in conjunction with low hemorrhage rates provide no compelling evidence that deviation from standard therapy is warranted. In addition, almost 40% of the enrolled patients had a large vessel occlusion, but data regarding location of obstruction and rates of recanalization is lacking and previous trial data would suggest that lower dose tPA has less success in recanalizing proximal vessel occlusions.7 Subgroup analyses exploring interaction of stroke subtype were not performed. In a clever allusion to the Disney movie Enchanted, Dr Sila stated that this well designed and executed trial shows us “how things really are and supports the continued use of guideline-based thrombolytic therapy for Asians with acute stroke.”
Regarding the question of whether or not to use low dose tPA in Asians suffering mild acute ischemic stroke, the answer seems to be no. The search remains active for alternatives to standard tPA, which remains the only option with proven efficacy. Will the idea of low dose tPA be abandoned? Likely not.
Evolution of Systemic Fibrinolytic Therapy
Despite being a negative study, it would be reasonable to conclude that low dose tPA is still better than placebo, potentially putting another therapy within reach for populations who would otherwise not be candidates for thrombolysis. Basic science research performed in China regarding mechanisms of fibrinogenolysis have identified the cell surface receptor annexin A2 as a target that can be manipulated to increase the efficiency of tPA action without increasing bleeding side effects.8 In mouse models, the addition of recombinant annexin A2 increased local concentrations of tPA-annexin A2-plasminogen complexes which amplified plasmin generation and subsequent attenuation of infarct size and improvement in neurological function. In the last several years, early phase 1 and 2 trials for an alternative fibrinolytic agent – tenecteplase – have suggested superior reperfusion and a similar safety profile to tPA.9-11 There is ongoing investigation into the widespread physiologic effects of this drug, but feasibility and safety have been demonstrated. Phase 3 efficacy trials are pending.
- Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med. 2016. doi: 10.1056/NEJMoa1515510.
- Mori E, Minematsu K, Nakagawara J, et al. Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral artery occlusion: Japan alteplase clinical trial II (J-ACT II). Stroke. 2010;41(3):461-465.
- Yamaguchi T, Mori E, Minematsu K, et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan alteplase clinical trial (J-ACT). Stroke. 2006;37(7):1810-1815.
- Kern R, Nagayama M, Toyoda K, Steiner T, Hennerici MG, Shinohara Y. Comparison of the european and japanese guidelines for the management of ischemic stroke. Cerebrovasc Dis. 2013;35(5):402-418.
- Ng KW, Sharma VK. Low-dose versus standard-dose tissue plasminogen activator for intravenous thrombolysis in asian acute ischemic stroke patients. Stroke. 2010;41(8):e545-6; author reply e547-8.
- Sila C. Finding the right t-PA dose for asians with acute ischemic stroke. N Engl J Med. 2016. doi: 10.1056/NEJMe1605228.
- Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893-903.
- Jiang Y, Fan X, Yu Z, et al. Combination low-dose tissue-type plasminogen activator plus annexin A2 for improving thrombolytic stroke therapy. Front Cell Neurosci. 2015;9.
- Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099-1107.
- Huang X, MacIsaac R, Thompson JL, et al. Tenecteplase versus alteplase in stroke thrombolysis: An individual patient data meta-analysis of randomized controlled trials. Int J Stroke. 2016. doi:10.1177/1747493016641112.
- Zerna C, Hegedus J, Hill MD. Evolving treatments for acute ischemic stroke. Circ Res. 2016;118(9):1425-1442.