Key design elements of successful acute ischemic stroke treatment trials

Neurological Research and Practice - Tập 5 Số 1
Laetitia Yperzeele1, Ashkan Shoamanesh2, Y. Vishnu Venugopalan3, Sherita Chapman4, Michael V. Mazya5, Marina Charalambous6, Valeria Caso7, Werner Hacke8, Philip M Bath9, Ivan Koltsov10
1Antwerp NeuroVascular Center and Stroke Unit, Department of Neurology, University Hospital Antwerp, Edegem, Belgium
2Division of Neurology, McMaster University / Population Health Research Institute, Hamilton, Canada
3Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
4Department of Neurology, University of Virginia, Charlottesville, USA
5Department of Neurology, Karolinska University Hospital, Stockholm, Sweden
6Department of Rehabilitation Sciences, Cyprus University of Technology, Limassol, Cyprus
7Stroke Unit, Santa Maria della Misericordia Hospital University of Perugia, Perugia, Italy
8Department of Neurology, Ruprechts Karl University, Heidelberg, Germany
9Stroke Trials Unit, Mental Health & Clinical Neuroscience, University of Nottingham, Nottingham, UK
10Cerebrovascular Diseases Laboratory, Pirogov Russian National Research Medical University, Moscow, Russia

Tóm tắt

Abstract Purpose We review key design elements of positive randomized controlled trials (RCTs) in acute ischemic stroke (AIS) treatment and summarize their main characteristics. Method We searched Medline, Pubmed and Cochrane databases for positive RCTs in AIS treatment. Trials were included if (1) they had a randomized controlled design, with (at least partial) blinding for endpoints, (2) they tested against placebo (or on top of standard therapy in a superiority design) or against approved therapy; (3) the protocol was registered and/or published before trial termination and unblinding (if required at study commencement); (4) the primary endpoint was positive in the intention to treat analysis; and (5) the study findings led to approval of the investigational product and/or high ranked recommendations. A topical approach was used, therefore the findings were summarized as a narrative review. Findings Seventeen positive RCTs met the inclusion criteria. The majority of trials included less than 1000 patients (n = 15), had highly selective inclusion criteria (n = 16), used the modified Rankin score as a primary endpoint (n = 15) and had a frequentist design (n = 16). Trials tended to be national (n = 12), investigator-initiated and performed with public funding (n = 11). Discussion Smaller but selective trials are useful to identify efficacy in a particular subgroup of stroke patients. It may also be of advantage to limit the number of participating countries and centers to avoid heterogeneity in stroke management and bureaucratic burden. Conclusion The key characteristics of positive RCTs in AIS treatment described here may assist in the design of further trials investigating a single intervention with a potentially high effect size.

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Tài liệu tham khảo

Chamorro, Á., Lo, E. H., Renú, A., van Leyen, K., & Lyden, P. D. (2021). The future of neuroprotection in stroke. Journal of Neurology, Neurosurgery, and Psychiatry, 92(2), 129–135. https://doi.org/10.1136/jnnp-2020-324283

Paul, S., & Candelario-Jalil, E. (2021). Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies. Experimental Neurology, 335, 113518. https://doi.org/10.1016/j.expneurol.2020.113518

Bath, P. M., Appleton, J. P., & England, T. (2020). The hazard of negative (not neutral) trials on treatment of acute stroke: A review. JAMA Neurology, 77(1), 114–124. https://doi.org/10.1001/jamaneurol.2019.4107

Ginsberg, M. D. (2008). Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology, 55(3), 363–389. https://doi.org/10.1016/j.neuropharm.2007.12.007

Lees, K. R., Zivin, J. A., Ashwood, T., Davalos, A., Davis, S. M., Diener, H.-C., Grotta, J., Lyden, P., Shuaib, A., Hårdemark, H.-G., Wasiewski, W. W., Stroke-Acute Ischemic NXY Treatment (SAINT I) Trial Investigators. (2006). NXY-059 for acute ischemic stroke. The New England Journal of Medicine, 354(6), 588–600. https://doi.org/10.1056/NEJMoa052980

Shuaib, A., Lees, K. R., Lyden, P., Grotta, J., Davalos, A., Davis, S. M., Diener, H.-C., Ashwood, T., Wasiewski, W. W., Emeribe, U., & Trial Investigators, S. A. I. N. T. I. I. (2007). NXY-059 for the treatment of acute ischemic stroke. The New England Journal of Medicine, 357(6), 562–571. https://doi.org/10.1056/NEJMoa070240

Chamorro, A., Amaro, S., Castellanos, M., Segura, T., Arenillas, J., Martí-Fábregas, J., Gállego, J., Krupinski, J., Gomis, M., Cánovas, D., Carné, X., Deulofeu, R., Román, L. S., Oleaga, L., Torres, F., Planas, A. M., & Investigators, U.R.I.C.O.-I.C.T.U.S. (2014). Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): A randomised, double-blind phase 2b/3 trial. The Lancet. Neurology, 13(5), 453–460. https://doi.org/10.1016/S1474-4422(14)70054-7

Hill, M. D., Goyal, M., Menon, B. K., Nogueira, R. G., McTaggart, R. A., Demchuk, A. M., Poppe, A. Y., Buck, B. H., Field, T. S., Dowlatshahi, D., van Adel, B. A., Swartz, R. H., Shah, R. A., Sauvageau, E., Zerna, C., Ospel, J. M., Joshi, M., Almekhlafi, M. A., Ryckborst, K. J., … ESCAPE-NA1 Investigators. (2020). Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): A multicentre, double-blind, randomised controlled trial. Lancet (London, England), 395(10227), 878–887. https://doi.org/10.1016/S0140-6736(20)30258-0

Albers, G. W., Goldstein, L. B., Hess, D. C., Wechsler, L. R., Furie, K. L., Gorelick, P. B., Hurn, P., Liebeskind, D. S., Nogueira, R. G., Saver, J. L., STAIR VII Consortium. (2011). Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke, 42(9), 2645–2650. https://doi.org/10.1161/STROKEAHA.111.618850

Fisher, M., Feuerstein, G., Howells, D. W., Hurn, P. D., Kent, T. A., Savitz, S. I., Lo, E. H., STAIR Group. (2009). Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke, 40(6), 2244–2250. https://doi.org/10.1161/STROKEAHA.108.541128

Stroke Pre-Clinical Assessment Network (SPAN). Retrieved November 11, 2021, from https://spannetwork.org/

Bath, P. M. W., Macleod, M. R., & Green, A. R. (2009). Emulating multicentre clinical stroke trials: A new paradigm for studying novel interventions in experimental models of stroke. International Journal of Stroke: Official Journal of the International Stroke Society, 4(6), 471–479. https://doi.org/10.1111/j.1747-4949.2009.00386.x

CAST (Chinese Acute Stroke Trial) Collaborative Group. (1997). CAST: Randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet (London, England), 349(9066), 1641–1649.

International Stroke Trial Collaborative Group. (1997). The International Stroke Trial (IST): A randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet (London, England), 349(9065), 1569–1581. https://doi.org/10.1016/S0140-6736(97)04011-7

Clark, W. M., Albers, G. W., Madden, K. P., & Hamilton, S. (2000). The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): Results of a double-blind, placebo-controlled, multicenter study. Stroke, 31(4), 811–816. https://doi.org/10.1161/01.str.31.4.811

Clark, W. M., Wissman, S., Albers, G. W., Jhamandas, J. H., Madden, K. P., & Hamilton, S. (1999). Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS study: A randomized controlled trial. Alteplase thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA, 282(21), 2019–2026. https://doi.org/10.1001/jama.282.21.2019

Donnan, G. A., Davis, S. M., Chambers, B. R., Gates, P. C., Hankey, G. J., McNeil, J. J., Rosen, D., Stewart-Wynne, E. G., & Tuck, R. R. (1996). Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA, 276(12), 961–966.

Hacke, W., Donnan, G., Fieschi, C., Kaste, M., von Kummer, R., Broderick, J. P., Brott, T., Frankel, M., Grotta, J. C., Haley, E. C., Kwiatkowski, T., Levine, S. R., Lewandowski, C., Lu, M., Lyden, P., Marler, J. R., Patel, S., Tilley, B. C., Albers, G., Bluhmki, E., et al. (2004). Association of outcome with early stroke treatment: Pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet (London, England), 363(9411), 768–774. https://doi.org/10.1016/S0140-6736(04)15692-4

Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Dávalos, A., Guidetti, D., Larrue, V., Lees, K. R., Medeghri, Z., Machnig, T., Schneider, D., von Kummer, R., Wahlgren, N., Toni, D., ECASS Investigators. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. The New England Journal of Medicine, 359(13), 1317–1329. https://doi.org/10.1056/NEJMoa0804656

Hacke, W., Kaste, M., Fieschi, C., Toni, D., Lesaffre, E., von Kummer, R., Boysen, G., Bluhmki, E., Höxter, G., & Mahagne, M. H. (1995). Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA, 274(13), 1017–1025.

Hacke, W., Kaste, M., Fieschi, C., von Kummer, R., Davalos, A., Meier, D., Larrue, V., Bluhmki, E., Davis, S., Donnan, G., Schneider, D., Diez-Tejedor, E., & Trouillas, P. (1998). Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet (London, England), 352(9136), 1245–1251. https://doi.org/10.1016/s0140-6736(98)08020-9

Multicenter Acute Stroke Trial—Europe Study Group, Hommel, M., Cornu, C., Boutitie, F., & Boissel, J. P. (1996). Thrombolytic therapy with streptokinase in acute ischemic stroke. The New England Journal of Medicine, 335(3), 145–150. https://doi.org/10.1056/NEJM199607183350301

Multicentre Acute Stroke Trial—Italy (MAST-I) Group. (1995). Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet (London, England), 346(8989), 1509–1514.

National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. (1995). Tissue plasminogen activator for acute ischemic stroke. The New England Journal of Medicine, 333(24), 1581–1587. https://doi.org/10.1056/NEJM199512143332401

Hacke, W., Albers, G., Al-Rawi, Y., Bogousslavsky, J., Davalos, A., Eliasziw, M., Fischer, M., Furlan, A., Kaste, M., Lees, K. R., Soehngen, M., & Warach, S. (2005). DIAS Study Group. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke, 36(1), 66–73. https://doi.org/10.1161/01.STR.0000149938.08731.2c

Hacke, W., Furlan, A. J., Al-Rawi, Y., Davalos, A., Fiebach, J. B., Gruber, F., Kaste, M., Lipka, L. J., Pedraza, S., Ringleb, P. A., Rowley, H. A., Schneider, D., Schwamm, L. H., Leal, J. S., Söhngen, M., Teal, P. A., Wilhelm-Ogunbiyi, K., Wintermark, M., & Warach, S. (2009). Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurology, 8(2), 141–150. https://doi.org/10.1016/S1474-4422(08)70267-9

Furlan, A. J., Eyding, D., Albers, G. W., Al-Rawi, Y., Lees, K. R., Rowley, H. A., Sachara, C., Soehngen, M., Warach, S., & Hacke, W., DEDAS Investigators. (2006). Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke, 37(5), 1227–1231. https://doi.org/10.1161/01.STR.0000217403.66996.6d

Thomalla, G., Simonsen, C. Z., Boutitie, F., Andersen, G., Berthezene, Y., Cheng, B., Cheripelli, B., Cho, T.-H., Fazekas, F., Fiehler, J., Ford, I., Galinovic, I., Gellissen, S., Golsari, A., Gregori, J., Günther, M., Guibernau, J., Häusler, K. G., Hennerici, M., Kemmling, A., et al. (2018). MRI-guided thrombolysis for stroke with unknown time of onset. New England Journal of Medicine, 379(7), 611–622. https://doi.org/10.1056/NEJMoa1804355

Ma, H., Campbell, B. C. V., Parsons, M. W., Churilov, L., Levi, C. R., Hsu, C., Kleinig, T. J., Wijeratne, T., Curtze, S., Dewey, H. M., Miteff, F., Tsai, C.-H., Lee, J.-T., Phan, T. G., Mahant, N., Sun, M.-C., Krause, M., Sturm, J., Grimley, R., Chen, C.-H., et al. (2019). Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. New England Journal of Medicine, 380(19), 1795–1803. https://doi.org/10.1056/NEJMoa1813046

Ringleb, P., Bendszus, M., Bluhmki, E., Donnan, G., Eschenfelder, C., Fatar, M., Kessler, C., Molina, C., Leys, D., Muddegowda, G., Poli, S., Schellinger, P., Schwab, S., Serena, J., Toni, D., Wahlgren, N., Hacke, W., ECASS-4 study group. (2019). Extending the time window for intravenous thrombolysis in acute ischemic stroke using magnetic resonance imaging-based patient selection. International Journal of Stroke: Official Journal of the International Stroke Society, 14(5), 483–490. https://doi.org/10.1177/1747493019840938

Furlan, A., Higashida, R., Wechsler, L., Gent, M., Rowley, H., Kase, C., Pessin, M., Ahuja, A., Callahan, F., Clark, W. M., Silver, F., & Rivera, F. (1999). Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA, 282(21), 2003–2011. https://doi.org/10.1001/jama.282.21.2003

Gobin, Y. P., Starkman, S., Duckwiler, G. R., Grobelny, T., Kidwell, C. S., Jahan, R., Pile-Spellman, J., Segal, A., Vinuela, F., & Saver, J. L. (2004). MERCI 1: a phase 1 study of mechanical embolus removal in cerebral ischemia. Stroke, 35(12), 2848–2854. https://doi.org/10.1161/01.STR.0000147718.12954.60

Penumbra Pivotal Stroke Trial Investigators. (2009). The penumbra pivotal stroke trial: Safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke, 40(8), 2761–2768. https://doi.org/10.1161/STROKEAHA.108.544957

Nogueira, R. G., Lutsep, H. L., Gupta, R., Jovin, T. G., Albers, G. W., Walker, G. A., Liebeskind, D. S., Smith, W. S., TREVO 2 Trialists. (2012). Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): A randomised trial. Lancet (London, England), 380(9849), 1231–1240. https://doi.org/10.1016/S0140-6736(12)61299-9

Saver, J. L., Jahan, R., Levy, E. I., Jovin, T. G., Baxter, B., Nogueira, R. G., Clark, W., Budzik, R., Zaidat, O. O., & Trialists, S. W. I. F. T. (2012). Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): A randomised, parallel-group, non-inferiority trial. Lancet (London, England), 380(9849), 1241–1249. https://doi.org/10.1016/S0140-6736(12)61384-1

Broderick, J. P., Palesch, Y. Y., Demchuk, A. M., Yeatts, S. D., Khatri, P., Hill, M. D., Jauch, E. C., Jovin, T. G., Yan, B., Silver, F. L., von Kummer, R., Molina, C. A., Demaerschalk, B. M., Budzik, R., Clark, W. M., Zaidat, O. O., Malisch, T. W., Goyal, M., Schonewille, W. J., Mazighi, M., et al. (2013). Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. The New England Journal of Medicine, 368(10), 893–903. https://doi.org/10.1056/NEJMoa1214300

Ciccone, A., Valvassori, L., Nichelatti, M., Sgoifo, A., Ponzio, M., Sterzi, R., & Boccardi, E. (2013). Endovascular treatment for acute ischemic stroke. New England Journal of Medicine, 368(10), 904–913. https://doi.org/10.1056/NEJMoa1213701

Kidwell, C. S., Jahan, R., Gornbein, J., Alger, J. R., Nenov, V., Ajani, Z., Feng, L., Meyer, B. C., Olson, S., Schwamm, L. H., Yoo, A. J., Marshall, R. S., Meyers, P. M., Yavagal, D. R., Wintermark, M., Guzy, J., Starkman, S., & Saver, J. L. (2013). A trial of imaging selection and endovascular treatment for ischemic stroke. New England Journal of Medicine, 368(10), 914–923. https://doi.org/10.1056/NEJMoa1212793

Goyal, M., Almekhlafi, M., Menon, B., Hill, M., Fargen, K., Parsons, M., Bang, O. Y., Siddiqui, A., Andersson, T., Mendes, V., Davalos, A., Turk, A., Mocco, J., Campbell, B., Nogueira, R., Gupta, R., Murphy, S., Jovin, T., Khatri, P., Miao, Z., et al. (2014). Challenges of acute endovascular stroke trials. Stroke, 45(10), 3116–3122. https://doi.org/10.1161/STROKEAHA.114.006288

Berkhemer, O. A., Fransen, P. S. S., Beumer, D., van den Berg, L. A., Lingsma, H. F., Yoo, A. J., Schonewille, W. J., Vos, J. A., Nederkoorn, P. J., Wermer, M. J. H., van Walderveen, M. A. A., Staals, J., Hofmeijer, J., van Oostayen, J. A., Lycklama à Nijeholt, G. J., Boiten, J., Brouwer, P. A., Emmer, B. J., de Bruijn, S. F., van Dijk, L. C., et al. (2015). A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke. New England Journal of Medicine, 372(1), 11–20. https://doi.org/10.1056/NEJMoa1411587

Bracard, S., Ducrocq, X., Mas, J. L., Soudant, M., Oppenheim, C., Moulin, T., Guillemin, F., THRACE investigators. (2016). Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): A randomised controlled trial. The Lancet. Neurology, 15(11), 1138–1147. https://doi.org/10.1016/S1474-4422(16)30177-6

Campbell, B. C. V., Mitchell, P. J., Kleinig, T. J., Dewey, H. M., Churilov, L., Yassi, N., Yan, B., Dowling, R. J., Parsons, M. W., Oxley, T. J., Wu, T. Y., Brooks, M., Simpson, M. A., Miteff, F., Levi, C. R., Krause, M., Harrington, T. J., Faulder, K. C., Steinfort, B. S., Priglinger, M., et al. (2015). Endovascular therapy for ischemic stroke with perfusion-imaging selection. New England Journal of Medicine, 372(11), 1009–1018. https://doi.org/10.1056/NEJMoa1414792

Goyal, M., Demchuk, A. M., Menon, B. K., Eesa, M., Rempel, J. L., Thornton, J., Roy, D., Jovin, T. G., Willinsky, R. A., Sapkota, B. L., Dowlatshahi, D., Frei, D. F., Kamal, N. R., Montanera, W. J., Poppe, A. Y., Ryckborst, K. J., Silver, F. L., Shuaib, A., Tampieri, D., Williams, D., et al. (2015). Randomized assessment of rapid endovascular treatment of ischemic stroke. New England Journal of Medicine, 372(11), 1019–1030. https://doi.org/10.1056/NEJMoa1414905

Jovin, T. G., Chamorro, A., Cobo, E., de Miquel, M. A., Molina, C. A., Rovira, A., San Román, L., Serena, J., Abilleira, S., Ribó, M., Millán, M., Urra, X., Cardona, P., López-Cancio, E., Tomasello, A., Castaño, C., Blasco, J., Aja, L., Dorado, L., Quesada, H., et al. (2015). Thrombectomy within 8 hours after symptom onset in ischemic stroke. New England Journal of Medicine, 372(24), 2296–2306. https://doi.org/10.1056/NEJMoa1503780

Saver, J. L., Goyal, M., Bonafe, A., Diener, H.-C., Levy, E. I., Pereira, V. M., Albers, G. W., Cognard, C., Cohen, D. J., Hacke, W., Jansen, O., Jovin, T. G., Mattle, H. P., Nogueira, R. G., Siddiqui, A. H., Yavagal, D. R., Baxter, B. W., Devlin, T. G., Lopes, D. K., Reddy, V. K., et al. (2015). Stent-retriever thrombectomy after intravenous t-PA vs T-PA alone in stroke. New England Journal of Medicine, 372(24), 2285–2295. https://doi.org/10.1056/NEJMoa1415061

Martins, S. O., Mont’Alverne, F., Rebello, L. C., Abud, D. G., Silva, G. S., Lima, F. O., Parente, B. S. M., Nakiri, G. S., Faria, M. B., Frudit, M. E., de Carvalho, J. J. F., Waihrich, E., Fiorot, J. A., Cardoso, F. B., Hidalgo, R. C. T., Zétola, V. F., Carvalho, F. M., de Souza, A. C., Dias, F. A., Nogueira, R. G., et al. (2020). Thrombectomy for stroke in the public health care system of Brazil. New England Journal of Medicine, 382(24), 2316–2326. https://doi.org/10.1056/NEJMoa2000120

Albers, G. W., Marks, M. P., Kemp, S., Christensen, S., Tsai, J. P., Ortega-Gutierrez, S., McTaggart, R. A., Torbey, M. T., Kim-Tenser, M., Leslie-Mazwi, T., Sarraj, A., Kasner, S. E., Ansari, S. A., Yeatts, S. D., Hamilton, S., Mlynash, M., Heit, J. J., Zaharchuk, G., Kim, S., Carrozzella, J., et al. (2018). Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. New England Journal of Medicine, 378(8), 708–718. https://doi.org/10.1056/NEJMoa1713973

Nogueira, R. G., Jadhav, A. P., Haussen, D. C., Bonafe, A., Budzik, R. F., Bhuva, P., Yavagal, D. R., Ribo, M., Cognard, C., Hanel, R. A., Sila, C. A., Hassan, A. E., Millan, M., Levy, E. I., Mitchell, P., Chen, M., English, J. D., Shah, Q. A., Silver, F. L., Pereira, V. M., et al. (2018). Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. New England Journal of Medicine, 378(1), 11–21. https://doi.org/10.1056/NEJMoa1706442

Jüttler, E., Unterberg, A., Woitzik, J., Bösel, J., Amiri, H., Sakowitz, O. W., Gondan, M., Schiller, P., Limprecht, R., Luntz, S., Schneider, H., Pinzer, T., Hobohm, C., Meixensberger, J., & Hacke, W. (2014). Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. New England Journal of Medicine, 370(12), 1091–1100. https://doi.org/10.1056/NEJMoa1311367

NIH U.S. National Library of Medicine. ClinicalTrials.gov. Retrieved January 6, 2022, from https://clinicaltrials.gov/

De Deyn, P. P., Reuck, J. D., Deberdt, W., Vlietinck, R., & Orgogozo, J. M. (1997). Treatment of acute ischemic stroke with piracetam. Stroke, 28(12), 2347–2352. https://doi.org/10.1161/01.str.28.12.2347

ENOS Trial Investigators. (2015). Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): A partial-factorial randomised controlled trial. Lancet (London, England), 385(9968), 617–628. https://doi.org/10.1016/S0140-6736(14)61121-1

Lyden, P., Shuaib, A., Ng, K., Levin, K., Atkinson, R. P., Rajput, A., Wechsler, L., Ashwood, T., Claesson, L., Odergren, T., Salazar-Grueso, E., CLASS-I, H, T Investigators. (2002). Clomethiazole acute stroke study in ischemic stroke (CLASS-I): Final results. Stroke, 33(1), 122–128. https://doi.org/10.1161/hs0102.101478

Mendelow, A. D., Gregson, B. A., Fernandes, H. M., Murray, G. D., Teasdale, G. M., Hope, D. T., Karimi, A., Shaw, M. D. M., Barer, D. H., STICH investigators. (2005). Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): A randomised trial. Lancet (London, England), 365(9457), 387–397. https://doi.org/10.1016/S0140-6736(05)17826-X

Mendelow, A. D., Gregson, B. A., Rowan, E. N., Murray, G. D., Gholkar, A., Mitchell, P. M., & Investigators, S. T. I. C. H. I. I. (2013). Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): A randomised trial. Lancet (London, England), 382(9890), 397–408. https://doi.org/10.1016/S0140-6736(13)60986-1

Ricci, S., Celani, M. G., Cantisani, T. A., & Righetti, E. (2012). Piracetam for acute ischaemic stroke. The Cochrane Database of Systematic Reviews, 9, CD000419. https://doi.org/10.1002/14651858.CD000419.pub3

RIGHT-2 Investigators. (2019). Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): An ambulance-based, randomised, sham-controlled, blinded, phase 3 trial. Lancet (London, England), 393(10175), 1009–1020. https://doi.org/10.1016/S0140-6736(19)30194-1

Wahlgren, N. G., Ranasinha, K. W., Rosolacci, T., Franke, C. L., van Erven, P. M., Ashwood, T., & Claesson, L. (1999). Clomethiazole acute stroke study (CLASS): Results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke, 30(1), 21–28. https://doi.org/10.1161/01.str.30.1.21

Saver, J. L., & Gornbein, J. (2009). Treatment effects for which shift or binary analyses are advantageous in acute stroke trials. Neurology, 72(15), 1310–1315. https://doi.org/10.1212/01.wnl.0000341308.73506.b7

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Neurological Research and Practice

Tập 5 Số 1

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