It was an academic study organized and conducted by independent researchers with international collaboration by The George Institute, in Sydney, Australia and Brazil by the Hospital de Clinicas de Porto Alegre, it had a quasi-factorial, controlled and randomized design involving a group of 2 arms of comparative linked treatment, with the aim of providing an answer to 4 key questions in patients eligible for thrombolysis in the acute phase of stroke. (1) The low dose (0.6mg / kg) of intravenous recombinant tissue plasminogen activator (rtPA) provides benefits equivalent to the recommended dose of rtPA (0.9mg / kg); (2) Strict control of blood pressure (systolic target of 140-150mmHg) improves the outcome when compared to the value recommended in current guidelines (systolic blood pressure [SBP] target of 180mmHg); (3) The low dose of intravenous rtPA (0.6mg / kg) reduces the risk of symptomatic intracranial hemorrhage (ICHs); (4) The combination of strict control of blood pressure and low dose of rtPA reduces the risk of ICHs. Randomization was performed using an internet system developed by The George Institute, in Sydney, Australia, stratifying by location and time of symptom onset (<3h x less than or equal to 3h) and NIHSS (<10 x less than or equal to 10) to ensure balance in key prognostic factors. Most patients were eligible for the thrombolytic treatment arm, as the inclusion criterion is eligibility for rtPA, but only a proportion (~ 60%) of patients with acute stroke was expected to have a high BP and thus be eligible for the pressure treatment arm.
This study, which was conducted entirely independently of the pharmaceutical industry, compared two different doses of r-tPA (or Alteplase), the thrombolytic drug used to treat stroke. The clinical trial was published in the New England Journal of Medicine and the results confirmed the efficacy of thrombolytics in the treatment of stroke, and showed that a lower dose of the drug can be an even safer way to treat it, leading to less bleeding complications in some cases.
Briefly, the main findings of the study were:
Compared with the standard dose (0.9 mg / kg of weight), the reduced dose (0.6 mg / kg of weight) led to a reduction of approximately 1/3 of the cases of bleeding complications (bleeding in the brain).
After 90 days, there was a reduction in the number of patients who died from 10.3% with the conventional dose to 8.5% with a reduced dose of thrombolytic.
This additional safety benefit with the reduced dose was only overshadowed by a small increase in cases that remain with residual stroke sequelae in 3 months. Thus, for every 1000 patients treated with the reduced dose, 41 had more residual sequelae of stroke (help with dressing or walking) compared to the standard dose, however 19 fewer people died with this reduced dose. For this reason, the conventional dose (0.9 mg / kg) should continue to be the most commonly used.
One of the study’s secondary findings was that the risk of bleeding appears to be greater in patients who were already using antiplatelet drugs such as aspirin. In these cases, the use of the reduced dose would be a safer option and with similar efficacy compared to the conventional dose.
The study is integrated with RNPAVC and two researchers from the Octavio Pontes-Neto and Sheila Martins network, who coordinated the study in Brazil, were included among the study authors. These results can increase safety and favor the administration of thrombolytic treatment for stroke in the country, especially within the SUS.
The second phase of the ENCHANTED study was completed in October 2018 and the results were presented at the main session of the American stroke conference (ISC 2019) in Honolulu, USA in February 2019 and will simultaneously be published in THE LANCET magazine.
Highlights of scientific production:
1: Yoshimura S, Lindley RI, Carcel C, Sato S, Delcourt C, Wang X, Chalmers J, Anderson CS; ENCHANTED Investigators. NIHSS cut point for predicting outcome in supra- vs infratentorial acute ischemic stroke. Neurology. 2018 Oct 30;91(18):e1695-e1701. doi: 10.1212/WNL.0000000000006437. Epub 2018 Sep 28. PubMed PMID: 30266885.
2: Minhas JS, Wang X, Arima H, Bath PM, Billot L, Broderick JP, Donnan GA, Kim JS, Lavados PM, Lee TH, Martins SCO, Olavarría VV, Pandian JD, Pontes-Neto OM, Ricci S, Sato S, Sharma VK, Thang NH, Wang JG, Woodward M, Chalmers J, Anderson CS, Robinson TG; ENCHANTED Investigators. Lipid-Lowering Pretreatment and Outcome Following Intravenous Thrombolysis for Acute Ischaemic Stroke: A Post Hoc Analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study Trial. Cerebrovasc Dis. 2018;45(5-6):213-220. doi: 10.1159/000488911. Epub 2018 Apr 27. PubMed PMID: 29705803.
Link: www.ncbi.nlm.nih.gov/pubmed
3: Wang X, Robinson TG, Lee TH, Li Q, Arima H, Bath PM, Billot L, Broderick J, Demchuk AM, Donnan G, Kim JS, Lavados P, Lindley RI, Martins SO, Olavarria VV, Pandian JD, Parsons MW, Pontes-Neto OM, Ricci S, Sharma VK, Thang NH, Wang JG, Woodward M, Anderson CS, Chalmers J; Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) Investigators. Low-Dose vs Standard-Dose Alteplase for Patients With Acute Ischemic Stroke: Secondary Analysis of the ENCHANTED Randomized Clinical Trial. JAMA Neurol. 2017 Nov 1;74(11):1328-1335. doi: 10.1001/jamaneurol.2017.2286. PubMed PMID: 28973174; PubMed Central PMCID: PMC5822216.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822216/?report=reader
4: Robinson TG, Wang X, Arima H, Bath PM, Billot L, Broderick JP, Demchuk AM, Donnan GA, Kim JS, Lavados PM, Lee TH, Lindley RI, Martins SCO, Olavarria VV, Pandian JD, Parsons MW, Pontes-Neto OM, Ricci S, Sato S, Sharma VK, Nguyen TH, Wang JG, Woodward M, Chalmers J, Anderson CS; ENCHANTED Investigators. Low- Versus Standard-Dose Alteplase in Patients on Prior Antiplatelet Therapy: The ENCHANTED Trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Stroke. 2017;48(7):1877-83. doi: 10.1161/STROKEAHA.116.016274. Epub 2017 Jun 15. PubMed PMID: 28619989.
Link: https://www.ahajournals.org/doi/epub/10.1161/STROKEAHA.116.016274
5: Anderson CS, Robinson T, Lindley RI, Arima H, Lavados PM, Lee TH, Broderick JP, Chen X, Chen G, Sharma VK, Kim JS, Thang NH, Cao Y, Parsons MW, Levi C, Huang Y, Olavarría VV, Demchuk AM, Bath PM, Donnan GA, Martins S, Pontes-Neto OM, Silva F, Ricci S, Roffe C, Pandian J, Billot L, Woodward M, Li Q, Wang X, Wang J, Chalmers J; ENCHANTED Investigators and Coordinators. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med. 2016 Jun 16;374(24):2313-23. doi: 10.1056/NEJMoa1515510. Epub 2016 May 10. Erratum in: N Engl J Med. 2018 Apr 12;378(15):1465-1466. PubMed PMID: 27161018.
Link: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1515510?articleTools=true
6: Huang Y, Sharma VK, Robinson T, Lindley RI, Chen X, Kim JS, Lavados P, Olavarría V, Arima H, Fuentes S, Nguyen HT, Lee TH, Parsons MW, Levi C, Demchuk AM, Bath PM, Broderick JP, Donnan GA, Martins S, Pontes-Neto OM, Silva F, Pandian J, Ricci S, Stapf C, Woodward M, Wang J, Chalmers J, Anderson CS; ENCHANTED investigators. Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 × 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment. Int J Stroke. 2015 Jul;10(5):778-88. doi: 10.1111/ijs.12486. Epub 2015 Apr 2. PubMed PMID: 25832995.